Compositions, methods, and systems for the synthesis and use of imaging agents

ABSTRACT

The present invention provides compounds with imaging moieties for imaging a subject. The present invention also relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, a composition or plurality of imaging agents is enriched in  18 F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.15/884,833, filed on Jan. 31, 2018, which is a continuation of U.S.application Ser. No. 15/359,675, filed on Nov. 23, 2016, which is acontinuation of U.S. application Ser. No. 14/420,810, filed on Feb. 10,2015, which is a national stage filing under 35 U.S.C. § 371 ofInternational Application No. PCT/US2013/054268, filed on Aug. 9, 2013,which claims priority under 35 U.S.C. § 119(e) to U.S. provisionalpatent applications, U.S. Ser. No. 61/682,185, filed Aug. 10, 2012, andU.S. Ser. No. 61/794,277, filed Mar. 15, 2013, each of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful as imaging agents,compositions thereof, methods for the synthesis and use thereof, andprecursors thereto.

BACKGROUND OF THE INVENTION

Mitochondria are membrane-enclosed organelles distributed through thecytosol of most eukaryotic cells. Mitochondria are especiallyconcentrated in myocardial tissue.

Mitochondrial complex 1 (“MC-1”) is a membrane-bound protein complex of46 dissimilar subunits. This enzyme complex is one of threeenergy-transducing complexes that constitute the respiratory chain inmammalian mitochondria. This NADH-ubiquinone oxidoreductase is the pointof entry for the majority of electrons that traverse the respiratorychain, eventually resulting in the reduction of oxygen to water (Q. Rev.Biophys. 1992, 25, 253-324). Examples of inhibitors of MC-1 includedeguelin, piericidin A, ubicidin-3, rolliniastatin-1, rolliniastatin-2(bullatacin), capsaicin, pyridaben, fenpyroximate, amytal, MPP+,quinolines, and quinolones (BBA 1998, 1364, 222-235). Studies have shownthat interrupting the normal function of mitochondria couldadvantageously concentrate certain compounds in the mitochondria, andhence in the mitochondria-rich myocardial tissue. Compounds that includean imaging moiety (e.g., ¹⁸F) can be useful in determining such abuild-up of compounds, thereby providing valuable diagnostic markers formyocardial perfusion imaging. In addition, such compounds may findapplication for the diagnosis of coronary artery disease (CAD).

CAD is a major cause of death in modern industrialized countries, and ithas been found previously that assessments of regional myocardialperfusion at rest and during stress (exercise or pharmacologic coronaryvasodilation) are valuable for noninvasive diagnosis of CAD. Whilemyocardial perfusion imaging (MPI) with Positron Emission Tomography(PET) has been shown to be superior in some embodiments as compared tosingle photon emission computed tomography (SPECT), widespread clinicaluse of PET MPI has been limited by the previously available PETmyocardial perfusion tracers.

Several PET blood flow tracers, such as rubidium-82 (⁸²Rb) chloride,nitrogen-13 (¹³N) ammonia, and oxygen-15 (¹⁵O) water, have beendeveloped and validated for assessment of myocardial perfusion. ¹³N and¹⁵O are cyclotron-produced isotopes with short half-lives. Therefore,their use is limited to facilities with an on-site cyclotron. Although⁸²Rb is a generator-produced tracer, its short half-life, the high costof the generator, and the inability to perform studies in conjunctionwith treadmill exercise have made this tracer impractical for widespreaduse. Tracers that comprise ¹⁸F have, however, found application asimaging agents.

SUMMARY OF THE INVENTION

The present invention provides, in a broad sense, compounds, andcompositions thereof, that are useful as imaging agents or imaging agentprecursors, kits thereof, methods of use thereof, and methods ofsynthesizing the provided compounds.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, heterocyclyl or aryl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound;and

provided that when W is aryl, a) R³ is not halo, alkyl or haloalkyl, orb) at least one R⁶ is selected from the group consisting of alkynyloptionally substituted, alkenyl optionally substituted, alkylsubstituted with —CN, alkyl substituted with —C(═O)OR⁸, alkylsubstituted with —C(═O)R⁸, alkyl substituted with —N(R⁷)₂, —CN, —NO₂,—N(R⁷)₂, —C(═O)OR⁸, —OC(═O)R⁸, —C(═O)R⁸, —C(═O)N(R⁷)₂, and—N(R⁷)C(═O)R⁸.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, or heterocyclyl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

Q has the structure:

wherein each Y and each X is independently selected from the groupconsisting of C, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least oneY is not C or C(R⁶), optionally, wherein one X and/or one Y is absent;

each

is independently a single or double bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, unsubstitutedalkyl or alkyl optionally substituted with a moiety other than ahalogen, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, —CN, and —NO₂;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, or 5;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

each R⁴, R⁵, and R¹¹ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

q, and r are each independently 0, 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, —NO₂, haloalkyl,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), and —CH₂O;

each R⁴ and R⁵ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

p is 0, 1, 2, 3, or 4;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

R¹² is selected from the group consisting of alkynyl optionallysubstituted, alkenyl optionally substituted, alkyl substituted with —CN,alkyl substituted with —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkylsubstituted with —N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)R⁸, —C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R^(8′);

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R²⁰ is selected from the group consisting of hydrogen, heteroalkyloptionally substituted, alkoxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —CN, and —NO₂;

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and an imaging moiety, or optionally anytwo R²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl,  OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and an imaging moiety, or optionally anytwo R²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

R²⁹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted, provided at least one K isalkenylene, or alkynylene;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one imaging moiety is present in the compound.

In some embodiments, the compounds provided above are imaging agents. Insome embodiments, a pharmaceutical composition is provided comprising acompound described above and optionally a pharmaceutically acceptableexcipient. In some embodiments, a sterile aqueous solution is providedcomprising a compound as described above. In some embodiments, use of acompound as described above as an imaging agent is provided. In someembodiments, use of a compound as described above in myocardialperfusion imaging is provided. In some embodiments, use of a compound asdescribed above in the manufacture of a medicament for detecting,imaging or monitoring myocardial perfusion is provided. In someembodiments, a method of imaging a portion of a subject is providedcomprising administering to the subject a compound as described aboveand acquiring at least one image of a portion of the subject. In someembodiments, a method of imaging a portion of a subject is providedcomprising administering to a subject a compound as described above,detecting radiation emitted by the compound, and forming an imagetherefrom. In some embodiments, a diagnostic kit is provided comprisingone or more vials containing a precursor to a compound as describedabove and optionally other components. In some embodiments, a method ofimaging myocardial perfusion is provided comprising administering to apatient a compound as described above and scanning the patient usingdiagnostic imaging. In some embodiments, a method of detectingmyocardial perfusion is provided comprising administering to a patient acompound as described above and scanning the patient using diagnosticimaging. In some embodiments, a method of monitoring myocardialperfusion is provided comprising administering to a patient a compoundas described above and scanning the patient using diagnostic imaging. Insome embodiments, precursors to the compounds described above areprovided. In some embodiments, the at least one imaging agent isreplaced with at least one leaving group.

In some embodiments, a cassette for the preparation of an imaging agentis provided comprising the components arranged as shown in FIG. 17 .

In some embodiments, an apparatus for synthesizing an imaging agentcomprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order:

-   -   1) luer connections (2) to gas inlet and [¹⁸O]H₂O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) spike connection for acetonitrile;    -   4) empty syringe;    -   5) reservoir with solution of imaging agent precursor;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) syringe with solution of a stabilizing agent;    -   12) syringe with water;    -   13) final product vial;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

In some embodiments, an apparatus for synthesizing an imaging agentcomprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order:

-   -   1) luer connections (2) to gas inlet and [¹⁸O]H₂O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) reservoir with solution of imaging agent precursor;    -   4) empty syringe;    -   5) spike connection for acetonitrile;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) syringe with solution of a stabilizing agent;    -   12) syringe with water;    -   13) final product vial;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

In some embodiments, an apparatus for synthesizing an imaging agentcomprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order:

-   -   1) luer connections (2) to gas inlet and [¹⁸O]H₂O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) reservoir with solution of imaging agent precursor;    -   4) empty syringe;    -   5) spike connection for acetonitrile;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) final product vial;    -   12) syringe with water;    -   13) syringe with solution of a stabilizing agent    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

In some embodiments, an apparatus for synthesizing an imaging agentcomprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order:

-   -   1) luer connections (2) to gas inlet and [¹⁸O]H₂O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) spike connection for acetonitrile;    -   4) empty syringe;    -   5) reservoir with solution of imaging agent precursor;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) final product vial;    -   12) syringe with water;    -   13) syringe with solution of a stabilizing agent;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-15 show representative images of non-limiting compounds in rat.

FIG. 16 shows a flow chart describing a method for synthesizing animaging agent, according to some embodiments.

FIG. 17 shows a schematic representation of a cassette, with associatedcolumns and reagents for synthesizing an imaging agent using anautomated synthesis module, according to some embodiments.

Other aspects, embodiments, and features of the invention will becomeapparent from the following detailed description when considered inconjunction with the accompanying drawings. The accompanying figures areschematic and are not intended to be drawn to scale. For purposes ofclarity, not every component is labeled in every figure, nor is everycomponent of each embodiment of the invention shown where illustrationis not necessary to allow those of ordinary skill in the art tounderstand the invention. All patent applications and patentsincorporated herein by reference are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, will control.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides compounds, compositions thereof, systemscomprising such compounds, reagents, cassettes, methods, kits, andapparatuses for the synthesis and/or use of the compounds as imagingagents and precursors thereof. The imaging agents of the presentinvention may be used to image an area of interest in a subject,including, but not limited to, the heart, a portion of the heart, thecardiovascular system, cardiac vessels, brain, and other organs. In someembodiments, the imaging agent comprises an imaging moiety, wherein theimaging moiety is selected from the group consisting of ¹¹C, ¹³N, ¹⁸F,⁷⁶Br, ¹²³I ¹²⁴I, ¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga,and ⁶⁸Ga. In certain embodiments, the imaging agent comprises ¹⁸F as theimaging moiety. In certain embodiments, the area of the subject beingimaged is imaged by positron emission tomography (PET).

In some embodiments, the present invention provides methods of imaging,including methods of imaging of a subject that includes administering acomposition or formulation (e.g., that comprises an imaging agent asdescribed herein) to the subject by injection, infusion, or any otherknown method of administration, and imaging a region of the subject thatis of interest. Regions of interest may include, but are not limited to,the heart, cardiovascular system, cardiac vessels, blood vessels (e.g.,arteries, veins), brain, and other organs. Regions of interest may alsoinclude tumors or regions of the subject's body that may include atumor. A parameter of interest, such as blood flow, cardiac wall motion,or perfusion, can be imaged and detected using methods and/or systemsdescribed herein. An event of interest can be imaged and detected and/orother information may be determined using methods and/or systems of thedisclosure. In some embodiments, methods for evaluating perfusion,including myocardial perfusion, are provided.

Imaging Agents

In one aspect, the invention provides compounds useful as imaging agentsfor imaging an area of interest of a subject. In some embodiments, theimaging agent comprises an imaging moiety, wherein the imaging moiety isselected from the group consisting of ¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I,¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga. Incertain embodiments, the imaging agent is labeled with ¹⁸F and is usefulin PET imaging. In some embodiments, a compound is provided comprisingthe structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, heterocyclyl or aryl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound;and

provided that when W is aryl, a) R³ is not halo, alkyl, or haloalkyl, orb) at least one R⁶ is selected from the group consisting of alkynyloptionally substituted, alkenyl optionally substituted, alkylsubstituted with —CN, alkyl substituted with —C(═O)OR⁸, alkylsubstituted with —C(═O)R⁸, alkyl substituted with —N(R⁷)₂, —CN, —NO₂,—N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸, —C(═O)R⁸, —C(═O)N(R⁷)₂, and—N(R⁷)C(═O)R⁸.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, or heterocyclyl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, for a compound of Formula (I), W is aryl. In someembodiments, for a compound of Formula (I), W is a 5-membered or6-membered aryl group.

The following description of W groups may be used in connection with acompound of Formula (I) or (II), or as noted herein. In someembodiments, W is heteroaryl. In some embodiments, W is five-memberedheteroaryl. In some embodiments, W is six-membered heteroaryl. In someembodiments, W is moncyclic heteroaryl. In some embodiments, W isbicyclic heteroaryl. In some embodiments, W is tricyclic heteroaryl. Insome embodiments, W is naphthyl. In some embodiments, W is heterocyclyl.In some embodiments, W is:

wherein each X is independently selected from the group consisting of C,C(R⁶), C(R⁶)₂, N, NR⁷, O, and S; and wherein each

is independently a single or double bond, provided at least one X is notC or C(R⁶). In some embodiments, at least one X is N. In someembodiments, at least one X is N(R⁷). In some embodiments, at least oneX is O. In some embodiments, at least one X is S. In some embodiments, Wis:

wherein each X is independently C, C(R⁶) or N, provided at least one Xis not C or C(R⁶). In some embodiments, W is:

In some embodiments, W is:

wherein R^(6′) is halo or hydrogen. In some embodiments, R^(6′) isfluoro, chloro, bromo, or hydrogen. In some embodiments, R⁶ is—O(CH₂)_(j)I_(m), wherein I_(m) is an imaging moiety and j is 1, 2, 3,4, 5, or 6. In some embodiments, R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m) I_(m)is an imaging moiety and wherein each j is independently 1, 2, 3, 4, 5,or 6. In some cases, I_(m) is ¹⁸F. In some embodiments, W is:

In some embodiments, W is:

wherein each X is independently selected from the group consisting of C,C(R⁶), C(R⁶)₂, N, NR⁷, O, and S; and each

is independently a single or double bond, provided at least one X is notC or C(R⁶). In some embodiments, W is selected from the group consistingof:

For a compound of Formula (I) or (II), each of the W groups describedherein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, J,m, and n, or combinations thereof, as described herein.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

Q has the structure:

each Y and each X is independently selected from the group consisting ofC, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least one Y is not C orC(R⁶), and optionally, wherein one Y and/or one X may be absent;

each

is independently a single or double bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

The following description of Q groups may be used in connection with acompound of Formula (III), or as noted herein. In some embodiments, Qhas the structure:

wherein each Y and each X is independently selected from the groupconsisting of C, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least oneY is not C or C(R⁶). In some embodiments, one Y and/or one X may beabsent. In some embodiments, one Y is absent. In some embodiments, one Xis absent. In some embodiments, one Y and one X are absent. In someembodiments, one Y is absent and one Y is N. In some embodiments, one Yis absent and one Y is NR⁷. In some embodiments, one Y is absent and oneY is O. In some embodiments, one Y is absent and one Y is S. In someembodiments, one X is absent and one X is N. In some embodiments, one Xis absent and one X is NR⁷. In some embodiments, one X is absent and oneX is O. In some embodiments, one X is absent and one X is S. In someembodiments, for Q, at least one Y is NR⁷. In some embodiments, for Q,at least one of each of X and Y is NR⁷. In some embodiments, for Q, atleast one Y is N. In some embodiments, for Q, at least one of each of Xand Y is N. In some embodiments, for Q, at least one Y is O. In someembodiments, for Q, at least one Y is S. In some embodiments, for Q,each X is C or C(R⁶). In some embodiments, for Q, at least one X is notC or C(R⁶). In some embodiments, for Q, at least two Y are not C orC(R⁶). In some embodiments, for Q, at least one of each of X and Y isnot C or C(R⁶). In some embodiments, for Q, at least two X are not C orC(R⁶). In some embodiments, Q is:

For a compound of Formula (III), each of the Q groups described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, J, and n,or combinations thereof, as described herein.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, unsubstitutedalkyl or alkyl optionally substituted with a moiety other than ahalogen, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, —CN, and —NO₂;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, or 5;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

each R⁴, R⁵, and R¹¹ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

q, and r are each independently 0, 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound. Insome embodiments, In some embodiments, a compound is provided comprisingthe structure:

In some embodiments, a compound is provided comprising the structure:

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, —NO₂, haloalkyl,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷)₂, N(R⁷)C(═O), and —CH₂O;

each R⁴ and R⁵ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

n is 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

The following description of Z groups may be used in connection with acompound of Formula (V), (VI), or (VII). In some embodiments, Z is aryl.In some embodiments, Z is phenyl. In some embodiments, Z is naphthyl. Insome embodiments, Z is heteroaryl. In some embodiments, Z isfive-membered heteroaryl. In some embodiments, Z is six-memberedheteroaryl. In some embodiments, Z is moncyclic heteroaryl. In someembodiments, Z is bicyclic heteroaryl. In some embodiments, Z istricyclic heteroaryl. In some embodiments, Z is heterocyclyl. In someembodiments, Z is:

wherein each X is independently selected from the group consisting of C,C(R⁶), C(R⁶)₂, N, NR⁷, O, and S; and wherein each

is independently a single or double bond. In some embodiments, at leastone X is not C or C(R⁶). In some embodiments, at least one X is N. Insome embodiments, at least one X is N(R⁷). In some embodiments, at leastone X is O. In some embodiments, at least one X is S. In someembodiments, Z is:

wherein each X is independently C, C(R⁶), or N. In some embodiments, atleast one X is not C or C(R⁶). In some embodiments, at least one X is N.In some embodiments, Z is:

In some embodiments, Z is:

wherein R^(6′) is halo or hydrogen. In some embodiments, R^(6′) isfluoro, chloro, bromo, or hydrogen. In some embodiments, R⁶ is—O(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2, 3,4, 5, or 6. In some embodiments, R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6. In some embodiments, Z is:

In some embodiments, Z is:

each X is independently selected from the group consisting of C, C(R⁶),C(R⁶)₂, N, NR⁷, O, and S; and each

is independently a single or double bond. In some embodiments, at leastone X is not C or C(R⁶). In some embodiments, at least one X is N. Insome embodiments, at least one X is N(R⁷). In some embodiments, at leastone X is O. In some embodiments, at least one X is S. In someembodiments, Z is selected from the group consisting of:

In some embodiments, Z is:

each Y is independently selected from the group consisting of C, C(R⁶),C(R⁶)₂, N, NR⁷, O, and S; and each

is independently a single or double bond, optionally, wherein one Xand/or one Y is absent. In some embodiments, one Y and/or one X may beabsent. In some embodiments, one Y is absent. In some embodiments, one Xis absent. In some embodiments, one Y and one X are absent. In someembodiments, one Y is absent and one Y is N. In some embodiments, one Yis absent and one Y is NR⁷. In some embodiments, one Y is absent and oneY is O. In some embodiments, one Y is absent and one Y is S. In someembodiments, one X is absent and one X is N. In some embodiments, one Xis absent and one X is NR⁷. In some embodiments, one X is absent and oneX is O. In some embodiments, one X is absent and one X is S. In someembodiments, for Z, at least one Y is NR⁷. In some embodiments, for Z,at least one of each of X and Y is NR⁷. In some embodiments, for Z, atleast one Y is N. In some embodiments, for Z, at least one of each of Xand Y is N. In some embodiments, for Z, at least one Y is O. In someembodiments, for Z, at least one Y is S. In some embodiments, for Z,each X is C or C(R⁶). In some embodiments, for Z, at least one X is notC or C(R⁶). In some embodiments, for Z, at least two Y are not C orC(R⁶). In some embodiments, for Z, at least one of each of X and Y isnot C or C(R⁶). In some embodiments, for Z, at least two X are not C orC(R⁶). In some embodiments, Z is:

In some embodiments, Z is:

In some embodiments, Z is:

For a compound of Formula (V) or (VI), each of the Z groups describedherein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹,J, m, q, and r, or combinations thereof, as described herein. For acompound of Formula (VII), each of the Z groups described herein may becombined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, J, n, and m, orcombinations thereof, as described herein.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of consisting of N(R⁷), S, O,C(═O), C(═O)O, OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

p is 0, 1, 2, 3, or 4;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

R¹² is selected from the group consisting of alkynyl optionallysubstituted, alkenyl optionally substituted, alkyl substituted with —CN,alkyl substituted with —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkylsubstituted with —N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸,—C(═O)R⁸, —C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R⁸;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

The following description of R¹ groups may be used in connection with acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).In some embodiments, R¹ is selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, aryl optionally substituted, heteroaryl optionallysubstituted, and an imaging moiety. In some embodiments, R¹ is hydrogen.In some embodiments, R¹ is alkyl optionally substituted. In someembodiments, R¹ is unsubstituted alkyl. In some embodiments, R¹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In someembodiments, R¹ is t-butyl. In some embodiments, R¹ is heteroalkyloptionally substituted. In some embodiments, R¹ is unsubstitutedheteroalkyl. In some embodiments, R¹ is —[C(R′)₂]_(j)OH, wherein j is 1,2, 3, 4, 5, or 6, and each R¹ is the same or different and is hydrogenor alkyl optionally substituted. In some embodiments, R¹ is—C(CH₃)₂CH₂OH. In some embodiments, R¹ is alkoxy optionally substituted.In some embodiments, R¹ is alkoxyalkyl optionally substituted. In someembodiments, R¹ is aryl optionally substituted. In some embodiments, R¹is unsubstituted aryl. In some embodiments, R¹ is phenyl optionallysubstituted. In some embodiments, R¹ is unsubstituted phenyl. In someembodiments, R¹ is cycloalkyl optionally substituted. In someembodiments, R¹ is unsubstituted cycloalkyl. In some embodiments, R¹ iscyclohexyl optionally substituted. In some embodiments, R¹ isunsubstituted cyclohexyl. In some embodiments, R¹ is cyclopentyloptionally substituted. In some embodiments, R¹ is unsubstitutedcyclopentyl. For a compound of Formula (I) or (II) each of the R¹ groupsdescribed herein may be combined with any R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R^(9′), J, W, m, and n, or combinations thereof, as describedherein. For a compound of Formula (III), each of the R¹ groups describedherein may be combined with any R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′),J, Q, and n, or combinations thereof, as described herein. For acompound of Formula (IV), each of the R¹ groups described herein may becombined with any R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, m, and n,or combinations thereof, as described herein. For a compound of Formula(V) or (VI), each of the R¹ groups described herein may be combined withany R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R11, J, Z, m, q, and r, orcombinations thereof, as described herein. For a compound of Formula(VII), each of the R¹ groups described herein may be combined with anyR², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, Z, n, and m, or combinationsthereof, as described herein. For a compound of Formula (VIII), each ofthe R¹ groups described herein may be combined with any R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R^(9′), R12, J, p, and n, or combinations thereof, asdescribed herein.

The following description of R² groups may be used in connection with acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).In some embodiments, R² is selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, aryl optionally substituted, heteroaryl optionallysubstituted, halo, haloalkyl, —NO₂, and an imaging moiety. In someembodiments, R² is hydrogen. In some embodiments, R² is alkyl optionallysubstituted. In some embodiments, R² is unsubstituted alkyl. In someembodiments, R² is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,or t-butyl. In some embodiments, R² is aryl optionally substituted. Insome embodiments, R² is unsubstituted aryl. In some embodiments, R² isphenyl optionally substituted. In some embodiments, R² is unsubstitutedphenyl. In some embodiments, R² is cycloalkyl optionally substituted. Insome embodiments, R² is unsubstituted cycloalkyl. In some embodiments,R² is cyclohexyl optionally substituted. In some embodiments, R² isunsubstituted cyclohexyl. Each of the R² groups described herein may becombined with any R¹, R³, R⁴, R⁵, R⁶, R¹², J, Q, W, and/or m, orcombinations thereof, as described herein. For a compound of Formula (I)or (II), each of the R² groups described herein may be combined with anyR¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, W, m, and n, or combinationsthereof, as described herein. For a compound of Formula (III), each ofthe R² groups described herein may be combined with any R¹, R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R^(9′), J, Q, and n, or combinations thereof, asdescribed herein. For a compound of Formula (IV), each of the R² groupsdescribed herein may be combined with any R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R^(9′), J, m, and n, or combinations thereof, as described herein.For a compound of Formula (V) or (VI), each of the R² groups describedherein may be combined with any R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′),R11, J, Z, m, q, and r, or combinations thereof, as described herein.For a compound of Formula (VII), each of the R² groups described hereinmay be combined with any R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, Z,n, and m, or combinations thereof, as described herein. For a compoundof Formula (VIII), each of the R² groups described herein may becombined with any R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹², J, p, andn, or combinations thereof, as described herein.

The following description of R³ groups may be used in connection with acompound of Formula (I), (II), (IV), (V), (VI), (VII), or (VIII). Insome embodiments, R³ is selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —CN, —NO₂, and an imaging moiety. In some embodiments, R³ isH. In some embodiments, R³ is alkyl optionally substituted. In someembodiments, R³ is alkyl optionally substituted with a moiety other thana halogen. In some embodiments, R³ is unsubstituted alkyl. In someembodiments, R³ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,or t-butyl. In some embodiments, R³ is methyl. In some embodiments, R³is i-propyl. In some embodiments, R³ is —CN. In some embodiments, R³ is—NO₂. In some embodiments, R³ is heteroalkyl optionally substituted. Insome embodiments, R³ is unsubstituted heteroalkyl. In some embodiments,R³ is aryl optionally substituted. In some embodiments, R³ isunsubstituted aryl. In some embodiments, R³ is phenyl optionallysubstituted. In some embodiments, R³ is unsubstituted phenyl. In someembodiments, R³ is halo. In some embodiments, R³ is F. In someembodiments, R³ is ¹⁸F. In some embodiments, R³ is Cl. In someembodiments, R³ is Br. In some embodiments, R³ is I. In someembodiments, R³ is not halo. In some embodiments, R³ is not halo,haloalkyl optionally substituted, or an imaging moiety. In someembodiments, R³ is not haloalkyl optionally substituted. In someembodiments, R³ is an imaging moiety. In some embodiments R³ is not animaging moiety. Each of the R³ groups described herein may be combinedwith any R¹, R², R⁴, R⁵, R⁶, R¹², J, Q, W, and/or m, or combinationsthereof, as described herein. For a compound of Formula (I) or (II),each of the R³ groups described herein may be combined with any R¹, R²,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, W, m, and n, or combinations thereof,as described herein. For a compound of Formula (IV), each of the R³groups described herein may be combined with any R¹, R², R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), J, m, and n, or combinations thereof, as describedherein. For a compound of Formula (V) or (VI), each of the R³ groupsdescribed herein may be combined with any R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R^(9′), R¹¹, J, Z, m, q, and r, or combinations thereof, asdescribed herein. For a compound of Formula (VII), each of the R³ groupsdescribed herein may be combined with any R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R^(9′), J, Z, n, and m, or combinations thereof, as describedherein. For a compound of Formula (VIII), each of the R³ groupsdescribed herein may be combined with any R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R^(9′), R¹², J, p, and n, or combinations thereof, as describedherein.

The following description of R³ groups may be used in connection with acompound of Formula (III). In some embodiments, R³ is selected from thegroup consisting of hydrogen, unsubstituted alkyl or alkyl optionallysubstituted with a moiety other than a halogen, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, aryl optionally substituted, heteroaryl optionallysubstituted, —CN, and —NO₂. In some embodiments, R³ is alkyl optionallysubstituted with a moiety other than a halogen. In some embodiments, R³is unsubstituted alkyl. In some embodiments, R³ is methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments,R³ is methyl. In some embodiments, R³ is i-propyl. In some embodiments,R³ is —CN. In some embodiments, R³ is —NO₂. In some embodiments, R³ isheteroalkyl optionally substituted. In some embodiments, R³ isunsubstituted heteroalkyl. In some embodiments, R³ is aryl optionallysubstituted. In some embodiments, R³ is unsubstituted aryl. In someembodiments, R³ is phenyl optionally substituted. In some embodiments,R³ is unsubstituted phenyl. For a compound of Formula (III), each of theR³ groups described herein may be combined with any R¹, R², R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R^(9′), J, Q, and n, or combinations thereof, as describedherein.

The following description of R⁴ and R⁵ groups may be used in connectionwith a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or(VIII). In some embodiments, R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen, alkyl optionally substituted, andan imaging moiety, or optionally any two of R⁴ and R⁵ are joinedtogether to form a ring. In some embodiments, any two of R⁴ and R⁵ maybe joined together to form a ring. In some cases, the ring formed maycomprise a total of 4, 5, 6, 7, 8, or more, atoms. In some cases, thering comprises 5 or 6 atoms. In some embodiments, each of R⁴ and R⁵ isH. In some embodiments, at least one R⁴ and R⁵ is ²H. In someembodiments, each of R⁴ and R⁵ is ²H. In some embodiments, each of R⁴and R⁵ is H or alkyl optionally substituted. In some embodiments, eachof R⁴ and R⁵ is H or unsubstituted alkyl. In some embodiments, at leastone R⁴ or R⁵ is not H. For a compound of Formula (I) or (II), each ofthe R⁴ and/or R⁵ groups described herein may be combined with any R¹,R², R³, R⁶, R⁷, R⁸, R⁹, R^(9′), J, W, m, and n, or combinations thereof,as described herein. For a compound of Formula (III), each of the R⁴and/or R⁵ groups described herein may be combined with any R¹, R², R³,R⁶, R⁷, R⁸, R⁹, R^(9′), J, Q, and n, or combinations thereof, asdescribed herein. For a compound of Formula (IV), each of the R⁴ and/orR⁵ groups described herein may be combined with any R¹, R², R³, R⁶, R⁷,R⁸, R⁹, R^(9′), J, m, and n, or combinations thereof, as describedherein. For a compound of Formula (V) or (VI), each of the R⁴ and/or R⁵groups described herein may be combined with any R¹, R², R³, R⁶, R⁷, R⁸,R⁹, R^(9′), R¹¹, J, Z, m, q, and r, or combinations thereof, asdescribed herein. For a compound of Formula (VII), each of the R⁴ and/orR⁵ groups described herein may be combined with any R¹, R², R³, R⁶, R⁷,R⁸, R⁹, R^(9′), J, Z, n, and m, or combinations thereof, as describedherein. For a compound of Formula (VIII), each of the R⁴ and/or R⁵groups described herein may be combined with any R¹, R², R³, R⁶, R⁷, R⁸,R⁹, R^(9′), R¹², J, p, and n, or combinations thereof, as describedherein.

The following description of R⁴, R⁵, and R¹¹ groups may be used inconnection with a compound of Formula (VI). In some embodiments, R⁴, R⁵,and R¹¹ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴, R⁵, and R¹¹ are joined together to form aring. In some embodiments, any two of R⁴, R⁵, and R¹¹ may be joinedtogether to form a ring. In some cases, the ring formed may comprise atotal of 4, 5, 6, 7, 8, or more, atoms. In some cases, the ringcomprises 5 or 6 atoms. In some embodiments, each of R⁴, R⁵, and R¹¹ isH. In some embodiments, at least one R⁴, R⁵, and R¹¹ is ²H. In someembodiments, each of R⁴, R⁵, and R¹¹ is ²H. In some embodiments, each ofR⁴, R⁵, and R¹¹ is H or alkyl optionally substituted. In someembodiments, each of R⁴, R⁵, and R¹¹ is H or unsubstituted alkyl. Insome embodiments, at least one R⁴, R⁵, and R¹¹ is not H. For a compoundof Formula (VI), each of the R⁴, R⁵, and/or R¹¹ groups described hereinmay be combined with any R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R^(9′), J, Z, m, q,and r, or combinations thereof, as described herein.

The following description of R¹² groups may be used in connection with acompound of Formula (VIII). In some embodiments, R¹² is selected fromthe group consisting of alkynyl optionally substituted, alkenyloptionally substituted, alkyl substituted with —CN, alkyl substitutedwith —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkyl substituted with—N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸, —C(═O)R⁸,—C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R⁸, wherein each R⁷ is independentlyselected from the group consisting of hydrogen, alkyl optionallysubstituted, alkenyl optionally substituted, alkynyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, and animaging moiety, or optionally, any two R⁷ may be joined together to forma ring; and each R⁸ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, haloalkyl, and animaging moiety. In some embodiments, any two of R⁷ may be joinedtogether to form a ring. In some cases, the ring formed may comprise atotal of 4, 5, 6, 7, 8, or more, atoms. In some cases, the ringcomprises 5 or 6 atoms. In some embodiments, R¹² is alkynyl optionallysubstituted. In some embodiments, R¹² is unsubstituted alkynyl. In someembodiments, R¹² is alkenyl optionally substituted. In some embodiments,R¹² is unsubstituted alkenyl. In some embodiments, R¹² is alkylsubstituted with —C(═O)OR⁸. In some embodiments, R¹² is alkylsubstituted with —C(═O)R⁸. In some embodiments, R¹² is alkyl substitutedwith —N(R⁷)₂. In some embodiments, R¹² is —CN. In some embodiments, R¹²is —NO₂. In some embodiments, R¹² is —N(R⁷)₂. In some embodiments, R¹²is —C(═O)OR⁸. In some embodiments, R¹² is —OC(═O)R⁸. In someembodiments, R¹² is —C(═O)R⁸. In some embodiments, R¹² is —C(═O)N(R⁷)₂.In some embodiments, R¹² is —N(R⁷)C(═O)R⁸. In some embodiments, R¹² is—NO₂, —C(═O)(CH₂)_(u)I_(m), —C(═O)O(CH₂)_(u)I_(m), —CC(CH₂)_(u)I_(m), or—Si(alkyl)₂I_(m), wherein I_(m) is an imaging moiety and u is 1, 2, 3,4, 5, or 6. For a compound of Formula (VIII), each of the R¹² groupsdescribed herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), J, p, and n, or combinations thereof, as describedherein.

The following description of J groups may be used in connection with acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).In some embodiments, J is selected from the group consisting of N(R⁷),S, O, C(═O), C(═O)O, OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond,wherein each R⁷ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, alkenyl optionally substituted,alkynyl optionally substituted, heteroalkyl optionally substituted,alkoxy optionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring. In some embodiments, any two of R⁷ maybe joined together to form a ring. In some cases, the ring formed maycomprise a total of 4, 5, 6, 7, 8, or more, atoms. In some cases, thering comprises 5 or 6 atoms. In some embodiments, J is a bond. In someembodiments, J is O. In some embodiments, J is S. In some embodiments, Jis N(R⁷). In some embodiments, J is C(═O). In some embodiments, J isC(═O)O. In some embodiments, J is OC(═O). In some embodiments, J is—CH₂O. In some embodiments, J is N(R⁷) or C(═O)N(R⁷) and any two R⁷ arejoined together to form a ring. In some cases, the ring formed maycomprise a total of 4, 5, 6, 7, 8, or more, atoms. In some cases, thering comprises 5 or 6 atoms. For a compound of Formula (I) or (II), eachof the J groups described herein may be combined with any R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), W, m, and n, or combinations thereof, asdescribed herein. For a compound of Formula (III), each of the J groupsdescribed herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), Q, and n, or combinations thereof, as described herein.For a compound of Formula (IV), each of the J groups described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), m,and n, or combinations thereof, as described herein. For a compound ofFormula (V) or (VI), each of the J groups described herein may becombined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R11, Z, m,q, and r, or combinations thereof, as described herein. For a compoundof Formula (VIII), each of the J groups described herein may be combinedwith any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹², p, and n, orcombinations thereof, as described herein.

The following description of J and n groups may be used in connectionwith a compound of Formula (I), (II), (III), (IV), or (VIII). In someembodiments, n is 0. In some embodiments, n is 1. In some embodiments, nis 2. In some embodiments, n is 3. In some embodiments, J is O and n is0. In some embodiments, J is O, and n is 1. In some embodiments, J is O,and n is 2. In some embodiments, J is O and n is 3. In some embodiments,J is S and n is 0. In some embodiments, J is S, and n is 1. In someembodiments, J is S, and n is 2. In some embodiments, J is S and n is 3.Each of the J groups and/or n groups described herein may be combinedwith any R¹, R², R³, R⁴, R⁵, R⁶, R¹², Q, W, and/or m, or combinationsthereof, as described herein. For a compound of Formula (I) or (II),each of the J and/or n groups described herein may be combined with anyR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), W, and m, or combinationsthereof, as described herein. For a compound of Formula (III), each ofthe J and/or n groups described herein may be combined with any R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), and Q, or combinations thereof, asdescribed herein. For a compound of Formula (IV), each of the J and/or ngroups described herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R^(9′), and m, or combinations thereof, as described herein.For a compound of Formula (VIII), each of the J and/or n groupsdescribed herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), R¹², and p, or combinations thereof, as describedherein.

The following description of J, q, and/or r groups may be used inconnection with a compound of Formula (V) or (VI). In some embodiments,q is 0. In some embodiments, q is 1. In some embodiments, q is 2. Insome embodiments, q is 3. In some embodiments, r is 0. In someembodiments, r is 1. In some embodiments, r is 2. In some embodiments, ris 3. In some embodiments, q and r are each 0. In some embodiments, qand r are each 1. In some embodiments, J is O and q and r are each 0. Insome embodiments, J is O and q and r are each 1. In some embodiments, Jis O and q and r are each 2. In some embodiments, J is O and q and r areeach 3. In some embodiments, J is S and q and r are each 0. In someembodiments, J is S and q and r are each 1. In some embodiments, J is Sand q and r are each 2. In some embodiments, J is S and q and r are each3. In some embodiments, J is O, q is 0, and r is 0, 1, 2, or 3. In someembodiments, J is O, q is 1, and r is 0, 1, 2, or 3. In someembodiments, J is O, q is 2, and r is 0, 1, 2, or 3. In someembodiments, J is O, q is 3, and r is 0, 1, 2, or 3. For a compound ofFormula (V) or (VI), each of the J, q, and/or r groups described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′),R11, Z, and m, or combinations thereof, as described herein.

The following description of J and n groups may be used in connectionwith a compound of Formula (VII). In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, Jis O, and n is 1. In some embodiments, J is 0, and n is 2. In someembodiments, J is O and n is 3. In some embodiments, J is S, and n is 1.In some embodiments, J is S, and n is 2. In some embodiments, J is S andn is 3. For a compound of Formula (VII), each of the J and/or n groupsdescribed herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), Z, and m, or combinations thereof, as described herein.

In some embodiments, for a compound of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII), the compound comprises a single imagingmoiety. In some embodiments, for a compound of Formula (I), (II), (III),(IV) or (VII), the at least one imaging moiety is present in R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, or R⁹. In some embodiments, for a compound ofFormula (VIII), the at least one imaging moiety is present in R¹, R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ or R¹². In some embodiments, for a compound ofFormula (V) or (VI), the at least one imaging moiety is present in R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ or R¹¹. In some embodiments, for acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),the at least one imaging moiety is present in R¹, R², R³, R⁴, R⁵, or R⁶.In some embodiments, for a compound of Formula (I), (II), (III), (IV),(V), (VI), (VII), or (VIII), the at least one imaging moiety is presentin R⁶. As will be understood by those of ordinary skill in the art, whenreferring to an imaging moiety, the imaging moiety “is present” in agroup in embodiments wherein 1) the imaging moiety is the group (e.g.,R⁶ is an imaging moiety) or b) the group comprises the imaging moiety(e.g., R⁶ is substituted with an imaging moiety). In some embodiments,for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII),R¹, R², R³, R⁴, R⁵, or R⁶ comprises the at least one imaging moiety. Insome embodiments, for a compound of Formula (VIII), R¹, R², R³, R⁴, R⁵,R⁶, or R¹² comprises the at least one imaging moiety. In someembodiments, for a compound of Formula (I), (II), (III), (IV), (V),(VI), (VII), or (VIII), at least one R⁶ is substituted with the at leastone imaging moiety. In some embodiments, for a compound of Formula (I),(II), (IV), or (VII), R¹, R², R³, R⁴, R⁵, or R⁶ is the at least oneimaging moiety. In some embodiments, for a compound of Formula (III),R¹, R², R⁴, R⁵, or R⁶ is the at least one imaging moiety. In someembodiments, for a compound of Formula (V) or (VI), R¹, R², R³, R⁴, R⁵,R⁶, or R¹¹ is the at least one imaging moiety. In some embodiments, fora compound of Formula (VIII), R¹, R³, R⁴, R⁵, R⁶, or R¹² is the at leastone imaging moiety. In some embodiments, for a compound of Formula (I),(II), (IV), or (VII), R¹, R², R³, R⁴, R⁵, or R⁶ is not an imagingmoiety. In some embodiments, for a compound of Formula (III), R¹, R²,R⁴, R⁵, or R⁶ is not an imaging moiety. In some embodiments, for acompound of Formula (V) or (VI), R¹, R², R³, R⁴, R⁵, R⁶, or R¹¹ is notan imaging moiety. In some embodiments, for a compound of Formula(VIII), R¹, R³, R⁴, R⁵, R⁶, or R¹² is not an imaging moiety. In someembodiments, for a compound of Formula (I), (II), (III), (IV), (V),(VI), (VII), or (VIII), at least one R⁶ is an imaging moiety. For acompound of Formula (I) or (II), each of the placements of the imagingmoieties described herein may be combined with any R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R^(9′), J, W, m, and n, or combinations thereof, asdescribed herein. For a compound of Formula (III), each of theplacements of the imaging moieties described herein may be combined withany R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), Q, J, and n, orcombinations thereof, as described herein. For a compound of Formula(IV), each of the placements of the imaging moieties described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J,n, and m, or combinations thereof, as described herein. For a compoundof Formula (V) or (VI), each of the placements of the imaging moietiesdescribed herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R^(9′), R11, J, Z, m, q, and r, or combinations thereof, asdescribed herein. For a compound of Formula (VII), each of theplacements of the imaging moieties described herein may be combined withany R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), J, Z, n, and m, orcombinations thereof, as described herein. For a compound of Formula(VIII), each of the placements of the imaging moieties described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′),R12, J, p, and n, or combinations thereof, as described herein.

The following description of the imaging moiety may be used inconnection with a compound of Formula (I), (II), (III), (IV), (V), (VI),(VII), or (VIII). In some embodiments, the at least one imaging moietyis selected from the group consisting of ¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ⁸⁹Zr,¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and⁶⁸Ga. In some embodiments, the at least one imaging moiety is ¹⁸F.Imaging moieties are described in more detail herein.

The following description of R⁶ groups may be used in connection with acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).In some embodiments, for a compound of Formula (I), (II), (III), (IV),(V), (VI), (VII), or (VIII), all but one R⁶ is H. That is, all R⁶ are Hand one R⁶ is not H. In some cases, the one R⁶ which is not H issubstituted with the at least one imaging moiety. In some cases, the oneR⁶ which is not H is the at least one imaging moiety. In someembodiments, for a compound of Formula (I), (II), (III), (IV), (V),(VI), (VII), or (VIII), at least one R⁶ is alkyl optionally substituted,alkoxy optionally substituted, or alkoxyalkyl optionally substituted,each substituted with an imaging moiety. In some embodiments, for acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII),at least one R⁶ is —(CH₂)_(j)I_(m); wherein I_(m) is an imaging moietyand j is 1, 2, 3, 4, 5, or 6. In some cases, at least one R⁶ is—(CH₂)I_(m), —(CH₂)₂I_(m), —(CH₂)₃I_(m), —(CH₂)₄I_(m), —(CH₂)₅I_(m),—(CH₂)₆I_(m), —(CH₂)₇I_(m), —(CH₂)₈I_(m), —(CH₂)₉I_(m), or—(CH₂)₁₀I_(m). In some cases, at least one R⁶ is —(CH₂)¹⁸F, —(CH₂)₂ ¹⁸F,—(CH₂)₃ ¹⁸F, —(CH₂)₄ ¹⁸F, —(CH₂)₅ ¹⁸F, —(CH₂)₆ ¹⁸F, —(CH₂)₇ ¹⁸F, —(CH₂)₈¹⁸F, —(CH₂)₉ ¹⁸F, or —(CH₂)₁₀ ¹⁸F. In some embodiments, at least one R⁶is —O(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2,3, 4, 5, or 6. In some cases, at least one R⁶ is —O(CH₂)₅I_(m),—O(CH₂)₆I_(m), —O(CH₂)₇I_(m), —O(CH₂)₈I_(m), —O(CH₂)₉I_(m), or—O(CH₂)₁₀I_(m). In some cases, at least one R⁶ is —O(CH₂)¹⁸F, —O(CH₂)₂¹⁸F, —O(CH₂)₃ ¹⁸F, —O(CH₂)₄ ¹⁸F, —O(CH₂)₅ ¹⁸F, —O(CH₂)₆ ¹⁸F, —O(CH₂)₇¹⁸F, —O(CH₂)₈ ¹⁸F, —O(CH₂)₉ ¹⁸F, or —O(CH₂)₁₀ ¹⁸F. In some embodiments,at least one R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m); wherein I_(m) is animaging moiety and each j is independently 1, 2, 3, 4, 5, or 6. In someembodiments, at least one R⁶ is —(CH₂) O(CH₂)_(j)I_(m); wherein I_(m) isan imaging moiety and each j is independently 1, 2, 3, 4, 5, or 6. Insome cases, at least one R⁶ is —CH₂O(CH₂) I_(m), —CH₂O(CH₂)₂I_(m),—CH₂O(CH₂)₃I_(m), —CH₂O(CH₂)₄I_(m), —CH₂O(CH₂)₅I_(m), —CH₂O(CH₂)₆I_(m),—CH₂O(CH₂)₇I_(m), —CH₂O(CH₂)₈I_(m), —CH₂O(CH₂)₉I_(m), or—H₂O(CH₂)₁₀I_(m). In some cases, at least one R⁶ is —CH₂O(CH₂)₇ ¹⁸F,—CH₂O(CH₂)₂ ¹⁸F, —CH₂O(CH₂)₃ ¹⁸F, —CH₂O(CH₂)₄ ¹⁸F, —CH₂O(CH₂)₅ ¹⁸F,—CH₂O(CH₂)₆ ¹⁸F, —CH₂O(CH₂)₇ ¹⁸F, —CH₂O(CH₂)₈ ¹⁸F, —CH₂O(CH₂)₉ ¹⁸F, or—CH₂O(CH₂)₁₀ ¹⁸F. In some embodiments, at least one R⁶ is—C≡C—(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2,3, 4, 5, or 6. In some embodiments, at least one R⁶ is—[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety andeach j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, atleast one R⁶ is —O[(CH₂)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is animaging moiety and each j is independently 1, 2, 3, 4, 5, or 6. In someembodiments, at least one R⁶ is optionally substituted alkyl substitutedwith an imaging moiety. In some embodiments, at least one R⁶ is—C(═O)O(CH⁻²)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1,2, 3, 4, 5, or 6. In some embodiments, at least one R⁶ is—C(═O)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2,3, 4, 5, or 6. In some embodiments, at least one R⁶ is—(CH₂)_(j)NH(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and eachj is independently 1, 2, 3, 4, 5, or 6. In some embodiments, at leastone R⁶ is Si(R⁹)₂I_(m), wherein each R⁹ is alkyl optionally substitutedand wherein I_(m) is an imaging moiety. In some embodiments, at leastone R⁶ is B(R^(9′))₂I_(m), wherein each R^(9′) is alkyl optionallysubstituted and wherein I_(m) is an imaging moiety. In some embodiments,at least one R⁶ is selected from the group consisting of—C≡CH₂CH₂CH₂I_(m), —C≡C—H₂CH₂CH₂I_(m), —C≡C—CH₂I_(m), —CH₂I_(m),—(CH₂)₂I_(m), —(CH₂)₃I_(m), —(CH₂)₄I_(m), —(CH₂)₅I_(m), —(CH₂)₆I_(m),—OCH₂I_(m), —O(CH₂)₂I_(m), —O(CH₂)₃I_(m), —O(CH₂)₄I_(m), —O(CH₂)₅I_(m),—O(CH₂)₆I_(m), —CH₂O(CH₂)₂I_(m), —CH(CH₃)O(CH₂)₂I_(m), —CH₂O(CH₂)₃I_(m),—CD₂O(CH₂)₂I_(m), —(CH₂)₂O(CH₂)₂I_(m), —CHBrC(CH₃)₂I_(m),—CHClC(CH₃)₂I_(m), —CHFC(CH₃)₂I_(m), —C(═O)OCH₂I_(m),—C(═O)O(CH₂)₂I_(m), —C(═O)O(CH₂)₃I_(m), —CH₂NH(CH₂)₂I_(m),—CH₂NHCH₂I_(m), —CH₂O(CH₂)₂O(CH₂)₂I_(m), —CH₂O(CH₂)₂O(CH₂)₃I_(m),—O(CH₂)₂O(CH₂)₂I_(m), —C(═O)(CH₂)₂I_(m), and —C(═O)(CH₂)₃I_(m). In someembodiments, I_(m) is ¹⁸F. In some embodiments, at least one R⁶ isselected from the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive, and I_(m) isan imaging moiety. In some embodiments, at least one R⁶ is selected fromthe group consisting of:

wherein I_(m) is an imaging moiety. In some embodiments, at least one R⁶is selected from the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive. In someembodiments, at least one R⁶ is selected from the group consisting of:

In some embodiments, for a compound of Formula (I), (II), (III), (IV),(V), (VI), (VII), or (VIII), at least one R⁶ is optionally substitutedwith at least one ²H. In some embodiments, at least one R⁶ is Si(R⁹)₃.In some embodiments, at least one R⁶ is B(R^(9′))₃. In some embodiments,at least one R⁶ is —NO₂. In some embodiments, at least one R⁶ is halo.In some embodiments, at least one R⁶ is Cl. In some embodiments, atleast one R⁶ is Br. In some embodiments, at least one R⁶ is F. For acompound of Formula (I) or (II), each of the R⁶ groups described hereinmay be combined with any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), J, W,m, and n, or combinations thereof, as described herein. For a compoundof Formula (III), each of the R⁶ groups described herein may be combinedwith any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), Q, J, and n, orcombinations thereof, as described herein. For a compound of Formula(IV), each of the R⁶ groups described herein may be combined with anyR¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), J, m, and n, or combinationsthereof, as described herein. For a compound of Formula (V) or (VI),each of the R⁶ groups described herein may be combined with any R¹, R²,R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), R¹¹, J, Z, m, q, and r, or combinationsthereof, as described herein. For a compound of Formula (VII), each ofthe R⁶ groups described herein may be combined with any R¹, R², R³, R⁴,R⁵, R⁷, R⁸, R⁹, R^(9′), J, Z, n, and m, or combinations thereof, asdescribed herein. For a compound of Formula (VIII), each of the R⁶groups described herein may be combined with any R¹, R², R³, R⁴, R⁵, R⁷,R⁸, R⁹, R^(9′), R¹², J, p, and n, or combinations thereof, as describedherein.

In some embodiments, a compound of Formula (II) is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F. In some embodiments, a compound of Formula (IV) is of the formula:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F. In some embodiments, a compound of Formula (VIII) is of theformula:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F. In some embodiments, a compound of Formula (V) or (VI) is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F. In some embodiments, a compound of Formula (VII) is of the formula:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

In some embodiments, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof, wherein I_(m) is animaging moiety. In some embodiments, the I_(m) is ¹⁸F. In someembodiments, the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In some embodiments, eachF is ¹⁸F.

In some embodiments, the compound is:

In some embodiments, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof. In some embodiments, eachF is ¹⁸F.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R²⁰ is selected from the group consisting of hydrogen, heteroalkyloptionally substituted, alkoxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —CN, and —NO₂;

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and an imaging moiety, or optionally anytwo R²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one imaging moiety is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R²¹ and R²³ is independently selected from the group        consisting of hydrogen, alkyl optionally substituted,        heteroalkyl optionally substituted, alkoxy optionally        substituted, alkoxyalkyl optionally substituted, halo,        haloalkyl, and an imaging moiety, or optionally any two R²¹ or        any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

R²⁹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, —CN, —NO₂,and an imaging moiety;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted, provided at least one K isalkenylene or alkynylene;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one imaging moiety is present in the compound.

In some embodiments, a compound of Formula (IX) comprises the structure:

In some embodiments, a compound of Formula (X) comprises the structure:

The following description of R²⁰ groups may be used in connection with acompound of Formula (IX). In some embodiments, R²⁰ is selected from thegroup consisting of hydrogen, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —CN, and —NO₂. In some embodiments, R²⁰ is hydrogen. In someembodiments, R²⁰ is heteroalkyl optionally substituted. In someembodiments, R²⁰ is alkoxy optionally substituted. In some embodiments,R²⁰ is alkoxyalkyl optionally substituted. In some embodiments, R²⁰ ishalo. In some embodiments, R²⁰ is F. In some embodiments, R²⁰ is Cl. Insome embodiments, R²⁰ is Br. In some embodiments, R²⁰ is I. In someembodiments, R²⁰ is haloalkyl. In some embodiments, R²⁰ is aryloptionally substituted. In some embodiments, R²⁰ is unsubstituted aryl.In some embodiments, R²⁰ is phenyl optionally substituted. In someembodiments, R²⁰ is unsubstituted phenyl. In some embodiments, R²⁰ iscycloalkyl optionally substituted. For a compound of Formula (IX), eachof the R²⁰ groups described herein may be combined with any R⁷, R⁸, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, G, a, K, b, and c, or combinationsthereof, as described herein.

The following description of R²⁹ groups may be used in connection with acompound of Formula (X). In some embodiments, R²⁹ is selected from thegroup consisting of R²⁹ is selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, aryl optionally substituted, heteroaryl optionallysubstituted, halo, haloalkyl, —CN, —NO₂, and an imaging moiety. In someembodiments, R²⁹ is hydrogen. In some embodiments, R²⁹ is alkyloptionally substituted. In some embodiments, R²⁹ is unsubstituted alkyl.In some embodiments, R²⁹ is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, or t-butyl. In some embodiments, R²⁹ is methyl. In someembodiments, R²⁹ is heteroalkyl optionally substituted. In someembodiments, R²⁹ is alkoxy optionally substituted. In some embodiments,R²⁹ is alkoxyalkyl optionally substituted. In some embodiments, R²⁹ ishalo. In some embodiments, R²⁹ is F. In some embodiments, R²⁹ is Cl. Insome embodiments, R²⁹ is Br. In some embodiments, R²⁹ is I. In someembodiments, R²⁹ is haloalkyl. In some embodiments, R²⁹ is aryloptionally substituted. In some embodiments, R²⁹ is unsubstituted aryl.In some embodiments, R²⁹ is phenyl optionally substituted. In someembodiments, R²⁹ is unsubstituted phenyl. In some embodiments, R²⁹ iscycloalkyl optionally substituted. In some embodiments, R²⁹ is —CN. Insome embodiments, R²⁹ is —NO₂. In some embodiments, R²⁹ is an imagingmoiety For a compound of Formula (X), each of the R²⁹ groups describedherein may be combined with any R⁷, R⁸, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, G, a, K, b, and c, or combinations thereof, as describedherein.

The following description of R²¹ and R²³ groups may be used inconnection with a compound of Formula (IX) or (X). In some embodiments,R²¹ and R²³ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and an imaging moiety, or optionally anytwo R²¹ or any two R²³ may be joined together to form a ring. In someembodiments, any two of R²¹ and R²³ may be joined together to form aring. In some cases, the ring formed may comprise a total of 4, 5, 6, 7,8, or more, atoms. In some cases, the ring comprises 5 or 6 atoms. Insome embodiments, each of R²¹ and R²³ is H. In some embodiments, atleast one R²¹ and R²³ is ²H. In some embodiments, each of R²¹ and R²³ is²H. In some embodiments, each of R²¹ and R²³ is H or alkyl optionallysubstituted. In some embodiments, each of R²¹ and R²³ is H orunsubstituted alkyl. In some embodiments, at least one R²¹ and R²³ isnot H. In some embodiments, at least one R²¹ or R²³ is an imagingmoiety. For a compound of Formula (IX), each of the R²¹ and/or R²³groups described herein may be combined with any R⁷, R⁸, R²⁰, R²², R²⁴,R²⁵, R²⁶, R²⁷, R²⁸, G, a, K, b, and c, or combinations thereof, asdescribed herein. For a compound of Formula (X), each of the R²¹ and/orR²³ groups described herein may be combined with any R⁷, R⁸, R²², R²⁴,R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, G, a, K, b, and c, or combinations thereof, asdescribed herein.

The following description of R²⁴, R²⁵, R²⁶, and R²⁷ groups may be usedin connection with a compound of Formula (IX) or (X). In someembodiments, R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected fromthe group consisting of hydrogen, alkyl optionally substituted, alkenyloptionally substituted, alkynyl optionally substituted, heteroalkyloptionally substituted, alkoxy optionally substituted, aryloxyoptionally substituted, heteroaryloxy optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸,—C(═O)OR⁸, —OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imagingmoiety. In some embodiments, each of R²⁴, R²⁵, R²⁶, and R²⁷ are H. Insome embodiments, at least one R²⁴, R²⁵, R²⁶, and R²⁷ is not H. In someembodiments, each of R²⁴, R²⁵, R²⁶, and R²⁷ is H or alkyl optionallysubstituted. In some embodiments, each of R²⁴, R²⁵, R²⁶, and R²⁷ is H orunsubstituted alkyl. For a compound of Formula (IX), each of the R²⁴,R²⁵, R²⁶, and R²⁷ groups described herein may be combined with any R⁷,R⁸, R²⁰, R²¹, R²², R², R²⁸, G, a, K, b, and c, or combinations thereof,as described herein. For a compound of Formula (X), each of the R²⁴,R²⁵, R²⁶, and R²⁷ groups described herein may be combined with any R⁷,R⁸, R²¹, R²², R²³, R²⁸, R²⁹, G, a, K, b, and c, or combinations thereof,as described herein.

The following description of G groups may be used in connection with acompound of Formula (IX) or (X). In some embodiments, G is O, S, orNR²⁸. In some embodiments, G is O. In some embodiments, G is S. In someembodiments, G is NR²⁸, wherein R²⁸ is selected from the groupconsisting of hydrogen, alkyl optionally substituted, and heteroalkyloptionally substituted. In some embodiments, G is NH. In someembodiments, G is NR²⁸, wherein R²⁸ is H or alkyl optionallysubstituted. In some embodiments, G is NR²⁸, wherein R²⁸ is alkyloptionally substituted. In some embodiments, G is NR²⁸, wherein R²⁸ isunsubstituted alkyl. For a compound of Formula (IX), each of the Ggroups described herein may be combined with any R⁷, R⁸, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, a, K, b, and c, or combinations thereof,as described herein. For a compound of Formula (X), each of the G groupsdescribed herein may be combined with any R⁷, R⁸, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, a, K, b, and c, or combinations thereof, asdescribed herein.

The following description of a, b, and c variables may be used inconnection with a compound of Formula (IX) or (X). In some embodiments,a is 0. In some embodiments, wherein a is 1. In some embodiments, a is2. In some embodiments, a is 3. In some embodiments, a is 4. In someembodiments, b is 0. In some embodiments, wherein b is 1. In someembodiments, b is 2. In some embodiments, b is 3. In some embodiments, bis 4. In some embodiments, c is 1. In some embodiments, c is 2. In someembodiments, a is 1, b is 1, and c is 1. In some embodiments, a is 2, bis 2, and c is 1. In some embodiments, a is 2, b is 2, and c is 2. For acompound of Formula (IX), each of the a, b, and c variables describedherein may be combined with any R⁷, R⁸, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵,R²⁶, R²⁷, R²⁸, G, and K, or combinations thereof, as described herein.For a compound of Formula (X), each of the a, b, and c variablesdescribed herein may be combined with any R⁷, R⁸, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, G, and K, or combinations thereof, as describedherein.

The following description of groups may be used in connection with acompound of Formula (IX) or (X). In some embodiments, at least one K isalkynylene. In some embodiments, at least one K is alkenylene. In someembodiments,

has the structure:

wherein each e is independently 1, 2, 3, or 4. In some embodiments, eache is 1. For a compound of Formula (IX), each of the above groups may becombined with any R⁷, R⁸, R²⁰, R²¹, R²², R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, G, anda, or combinations thereof, as described herein. For a compound ofFormula (X), each of the above groups may be combined with any R⁷, R⁸,R²¹, R²², R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, G, and a, or combinationsthereof, as described herein.

The following description of R²² groups may be used in connection with acompound of Formula (IX) or (X). In some embodiments, R²² is selectedfrom the group consisting of hydrogen, alkyl optionally substituted,heteroalkyl optionally substituted, alkoxyalkyl optionally substituted,halo, haloalkyl, —OR²⁸, and an imaging moiety. In some embodiments, R²²is —Si(R⁹)₃ or —B(R^(9′))₃. In some embodiments, R²² is hydrogen. Insome embodiments, R²² is alkyl optionally substituted. In someembodiments, R²² is unsubstituted alkyl. In some embodiments, R²² isheteroalkyl optionally substituted. In some embodiments, R²² isunsubstituted heteroalkyl. In some embodiments, R²² is alkoxyalkyloptionally substituted. In some embodiments, R²² is unsubstitutedalkoxyalkyl. In some embodiments, R²² is halo. In some embodiments, R²²is F. In some embodiments, R²² is Cl. In some embodiments, R²² is Br. Insome embodiments, R²² is I. In some embodiments, R²² is haloalkyl. Insome embodiments, R²² is —OR²⁸, wherein R²⁸ is selected from the groupconsisting of hydrogen, alkyl optionally substituted, and heteroalkyloptionally substituted. In some embodiments, R²² is OH. In someembodiments, R²² is OR²⁸, wherein R²⁸ is H or alkyl optionallysubstituted. In some embodiments, R²² is OR²⁸, wherein R²⁸ is alkyloptionally substituted. In some embodiments, R²² is OR²⁸, wherein R²⁸ isunsubstituted alkyl. In some embodiments, R²² is an imaging moiety. Insome embodiments, R²² is substituted with an imaging moiety. In someembodiments, R²² is alkyl optionally substituted, alkoxy optionallysubstituted, or alkoxyalkyl optionally substituted, each substitutedwith an imaging moiety. In some embodiments, R²² is —(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and j is 1, 2, 3, 4, 5, or 6. In somecases, R²² is —(CH₂)I_(m), —(CH₂)₂I_(m), —(CH₂)₃I_(m), —(CH₂)₄I_(m),—(CH₂)₅I_(m), —(CH₂)₆I_(m), —(CH₂)₇I_(m), —(CH₂)₈I_(m), —(CH₂)₉I_(m), or—(CH₂)₁₀I_(m). In some cases, R²² is —(CH₂)¹⁸F, —(CH₂)₂ ¹⁸F, —(CH₂)₃¹⁸F, —(CH₂)₄ ¹⁸F, —(CH₂)₅ ¹⁸F, —(CH₂)₆ ¹⁸F, —(CH₂)₇ ¹⁸F, —(CH₂)₈ ¹⁸F,—(CH₂)₉ ¹⁸F, or —(CH₂)₁₀ ¹⁸F. In some embodiments, R²² is—O(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2, 3,4, 5, or 6. In some cases, R²² is —O(CH₂)_(j)I_(m), —O(CH₂)₂I_(m),—O(CH₂)₃I_(m), —O(CH₂)₄I_(m), —O(CH₂)₅I_(m), —O(CH₂)₆I_(m),—O(CH₂)₇I_(m), —O(CH₂)₈I_(m), —O(CH₂)₉I_(m), or —O(CH₂)₁₀I_(m). In somecases, R²² is —O(CH₂)¹⁸F, —O(CH₂)₂ ¹⁸F, —O(CH₂)₃ ¹⁸F, —O(CH₂)₄ ¹⁸F,—O(CH₂)₅ ¹⁸F, —O(CH₂)₆ ¹⁸F, —O(CH₂)₇ ¹⁸F, —O(CH₂)₈ ¹⁸F, —O(CH₂)₉ ¹⁸F, or—O(CH₂)₁₀ ¹⁸F. In some embodiments, R²² is —(CH₂)_(j)O(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6. In some embodiments, R²² is —(CH₂)O(CH₂)_(j)I_(m); whereinI_(m) is an imaging moiety and each j is independently 1, 2, 3, 4, 5, or6. In some cases, R²² is —CH₂O(CH₂)I_(m), —CH₂O(CH₂)₂I_(m),—CH₂O(CH₂)₃I_(m), —CH₂O(CH₂)₄I_(m), —CH₂O(CH₂)₅I_(m), —CH₂O(CH₂)₆I_(m),—CH₂O(CH₂)₇I_(m), —CH₂O(CH₂)₈I_(m), —CH₂O(CH₂)₉I_(m), or—CH₂O(CH₂)₁₀I_(m). In some cases, R²² is —CH₂O(CH₂) 18F, —CH₂O(CH₂)₂¹⁸F, —CH₂O(CH₂)₃ ¹⁸F, —CH₂O(CH₂)₄ ¹⁸F, —CH₂O(CH₂)₅ ¹⁸F, —CH₂O(CH₂)₆ ¹⁸F,—CH₂O(CH₂)₇ ¹⁸F, —CH₂O(CH₂)₈ ¹⁸F, —CH₂O(CH₂)₉ ¹⁸F, or —CH₂O(CH₂)₁₀ ¹⁸F.In some embodiments, R²² is —C≡C—(CH₂)_(j)I_(m); wherein I_(m) is animaging moiety and j is 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety andeach j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—O[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety andeach j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, R²² isoptionally substituted alkyl substituted with an imaging moiety. In someembodiments, R²² is —C(═O)O(CH₂)jI_(m); wherein I_(m) is an imagingmoiety and j is 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—C(═O)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2,3, 4, 5, or 6. In some embodiments, R²² is —(CH⁻²)_(j)NH(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6. In some embodiments, R²² is Si(R⁹)₂I_(m), wherein each R⁹ isalkyl optionally substituted and wherein I_(m) is an imaging moiety. Insome embodiments, R²² is B(R^(9′))₂I_(m), wherein each R^(9′) is alkyloptionally substituted and wherein I_(m) is an imaging moiety. In someembodiments, R²² is selected from the group consisting of—C≡C—CH₂CH₂CH₂I_(m), —C≡C—H₂CH₂I_(m), —C≡C CH₂I_(m), —CH₂I_(m),—(CH₂)₂I_(m), —(CH₂)₃I_(m), —(CH₂)₄I_(m), —(CH₂)₅I_(m), —(CH₂)₆I_(m),—OCH₂I_(m), —O(CH₂)₂I_(m), —O(CH₂)₃I_(m), —O(CH₂)₄I_(m), —O(CH₂)₅I_(m),—O(CH₂)₆I_(m), —CH₂O(CH₂)₂I_(m), —CH(CH₃)O(CH₂)₂I_(m), —CH₂O(CH₂)₃I_(m),—CD₂O(CH₂)₂I_(m), —(CH₂)₂O(CH₂)₂I_(m), —CHBrC(CH₃)₂I_(m),—CHClC(CH₃)₂I_(m), —CHFC(CH₃)₂I_(m), —C(═O)OCH₂I_(m),—C(═O)O(CH₂)₂I_(m), —C(═O)O(CH₂)₃I_(m), —CH₂NH(CH₂)₂I_(m),—CH₂NHCH₂I_(m), —CH₂O(CH₂)₂O(CH₂)₂I_(m), —CH₂O(CH₂)₂O(CH₂)₃I_(m),—O(CH₂)₂O(CH₂)₂I_(m), —C(═O)(CH₂)₂I_(m), and —C(═O)(CH₂)₃I_(m). In someembodiments, wherein I_(m) is ¹⁸F. In some embodiments, R²² is selectedfrom the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive, and I_(m) isan imaging moiety. In some embodiments, R²² is selected from the groupconsisting of:

wherein I_(m) is an imaging moiety. In some embodiments, R²² is selectedfrom the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive. In someembodiments, R²² is selected from the group consisting of:

For a compound of Formula (IX), each of the R²² groups described hereinmay be combined with any R⁷, R⁸, R²⁰, R²¹, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,G, a, K, b, and c, or combinations thereof, as described herein. For acompound of Formula (X), each of the R²² groups described herein may becombined with any R⁷, R⁸, R²¹, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁶, G, a,K, b, and c, or combinations thereof, as described herein.

In some embodiments, for a compound of Formula (IX), the at least oneimaging moiety is present in R⁷, R⁸, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, or R²⁸. In some embodiments, a compound of Formula (X) or (IX)comprises a single imaging moiety. In some embodiments, for a compoundof Formula (X), the at least one imaging moiety is present in R⁷, R⁸,R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, or R²⁹. In some embodiments, fora compound of Formula (X) or (IX), the at least one imaging moiety ispresent in R²². As noted above, as will be understood by those ofordinary skill in the art, when referring to an imaging moiety, theimaging moiety “is present” in a group in embodiments wherein 1) theimaging moiety is the group (e.g., R²² is an imaging moiety) or b) thegroup comprises the imaging moiety (e.g., R²² is substituted with animaging moiety). In some embodiments, for a compound of Formula (IX),R⁷, R⁸, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, or R²⁸ comprises the atleast one imaging moiety. In some embodiments, for a compound of Formula(X), R⁷, R⁸, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, or R²⁹ comprisesthe at least one imaging moiety. In some embodiments, for a compound ofFormula (IX), R⁷, R⁸, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, is the at leastone imaging moiety. In some embodiments, for a compound of Formula (X)R⁷, R⁸, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, or R²⁸ is the at least oneimaging moiety. For a compound of Formula (IX), each of the aboveplacements of the imaging moieties may be combined with any R⁷, R⁸, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, G, a, K, b, and c, orcombinations thereof, as described herein. For a compound of Formula(X), each of the above placements of the imaging moieties may becombined with any R⁷, R⁸, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,G, a, K, b, and c, or combinations thereof, as described herein.

The following description of the imaging moiety may be used inconnection with a compound of Formula (IX) and (X). In some embodiments,the at least one imaging moiety is selected from the group consisting of¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ⁸Zr, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵c, ¹¹¹In,⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga. In some embodiments, the at least oneimaging moiety is ¹⁸F. Imaging moieties are described in more detailherein.

In some embodiments, a compound of Formula (IX) is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

In some embodiments, a compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof, wherein I_(m) is animaging moiety. In some embodiments, I_(m) is ¹⁸F. In some embodiments,a compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In some embodiments, eachF is ¹⁸F. In some embodiments, a compound is:

or a pharmaceutically acceptable salt thereof. In some embodiments, eachF is ¹⁸F.

In some embodiments, a compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof. In some embodiments, eachF is ¹⁸F.

It should be understood, that any hydrogen molecule of a structuredescribed herein may, in some embodiments, may be optionally substitutedand/or enriched in ²H. In some cases, at least one ²H has beensubstituted for a ¹H.

As used herein, the term “imaging agent” refers to any chemical compoundthat includes an imaging moiety. Typically, the imaging agent may beadministered to a subject in order to provide information relating to atleast a portion of the subject (e.g., human). In some cases, an imagingagent may be used to highlight a specific area of a subject, renderingorgans, blood vessels, tissues, and/or other portions more detectableand/or more clearly imaged. By increasing the detectability and/or imagequality of the object being studied, the presence and extent of diseaseand/or injury can be determined. An “imaging moiety” refers to an atomor group of atoms that is capable of producing a detectable signalitself (e.g., radioisotopes), or upon exposure to an external source ofenergy (e.g., electromagnetic radiation, ultrasound, and the like). Incertain cases, the imaging moiety may alter its local chemical and/ormagnetic and/or electronic environment. Non-limiting examples of imagingmoieties include ¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ^(99m)Tc,⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, and ⁸⁹Zr. In some embodiments, theimaging moiety is associated with a group comprising the structure—B(R^(9′))₂I_(m) or —Si(R⁹)²I_(m), wherein I_(m) is an imaging moiety,optionally ¹⁸F. In some embodiments, the imaging moiety is directlyassociated (i.e., through a covalent bond) with a compound as describedherein (e.g., in the case of ¹⁸F, ⁷⁶Br, ¹²⁴I, or ¹³¹I). In someembodiments, the imaging moiety is associated with the compound throughnon-covalent interactions (e.g., electrostatic interactions). In someembodiments, the imaging moiety is associated with the compound througha chelator (e.g., in the case of ⁶⁴Cu, 89Zr, ^(99m)Tc, and ¹¹¹In).Chelators are described in more detail herein. In some embodiments, theimaging moiety is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,¹³¹I, ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In. In certain embodiments, theimaging moiety is ¹⁸F. In certain embodiments, the imaging moiety is⁷⁶Br. In certain embodiments, the imaging moiety is ¹²⁴I. In certainembodiments, the imaging moiety is ¹³¹I. In some cases, the imagingmoiety is ¹⁸F, ⁷⁶Br, or ¹²⁴I. In some cases, the imaging moiety is ¹⁸For ⁷⁶Br. In some cases, an imaging agent comprises a single imagingmoiety. In some cases, an imaging agent comprises more than one imagingmoiety (e.g., two imaging moieties). As used herein, the term “imagingagent” encompasses contrast agents. In some embodiments, an imagingagent is a contrast agent. The term “contrast agent” refers to a type ofimaging agent comprising an imaging moiety that produces a detectablesignal in response to an external source of energy. In certain cases,the contrast agent may comprise an imaging moiety that absorbs and/orreflects and/or transmits the external source of energy.

In some embodiments, a composition comprising a compound of theinvention or a plurality of compounds is enriched with compoundsincluding an isotope such as a radioisotope. In such a case, theplurality or composition may be referred to as being “isotopicallyenriched.” An “isotopically enriched” composition refers to acomposition comprising a percentage of one or more isotopes of anelement that is greater than the percentage of that isotope that occursnaturally. For example, a composition that is isotopically enriched witha fluoride species may be “isotopically enriched” with fluorine-18(¹⁸F). Thus, with regard to a plurality of compounds, when a particularatomic position is designated as ¹⁸F, it is to be understood that theabundance (or frequency) of ¹⁸F at that position (in the plurality) isgreater than the natural abundance (or frequency) of ¹⁸F, which isessentially zero.

In some embodiments, an atom designated as being enriched may have aminimum isotopic enrichment factor of about 0.001% (i.e., about 1 out of10⁵ atoms is the desired isotope of the atom), about 0.002%, about0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about0.008%, about 0.009%, about 0.01%, about 0.05%, about 0.1%, about 0.2%,about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 2%,about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, or greater. The minimum isotopic enrichment factor, in someinstances, may range from about 0.001% to about 1%. For example, inembodiments wherein the imaging moiety is fluorine, a fluorinedesignated as ¹⁸F may have a minimum isotopic enrichment factor of about0.001% (i.e., about 1 out of 10⁵ fluorine species is ¹⁸F), about 0.002%,about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%,about 0.008%, about 0.009%, about 0.01%, about 0.05%, about 0.1%, about0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, or greater. The isotopic enrichment of a composition orplurality of compounds provided herein can be determined usingconventional analytical methods known to one of ordinary skill in theart, including, for example, mass spectrometry and HPLC.

In some embodiments, compositions, methods, uses, and/or systemsdescribed herein include or use compounds described herein. In someembodiments, the compounds are imaging agents. In some embodiments, thecompounds are contrast agents. In some embodiments, the compounds areprecursor to imaging agents or contrast agents.

Chelators

In some cases, an imaging moiety may be associated with a compound asdescribed herein via association with a chelator (e.g., in embodimentswhere the imaging moiety is ⁶⁴Cu, ⁶⁸Ga, ⁸⁹Zr, ^(99m)Tc, ¹¹¹In). Thechelator is typically covalently attached to the compound. However, incertain embodiments, the chelator may be associated with the compoundthrough non-covalent interactions. The term chelator is given itsordinary meaning in the art and generally refers to a chemical moietycapable of complexing an imaging moiety (e.g., a metal ion and/orradionuclide), wherein the complex is stable under physiologicalconditions. For example, generally, the imaging moiety remains complexedwith the chelator in vivo. In some embodiments, the chelator is themoiety or group on a compound that binds to an imaging moiety throughone or more donor atoms and/or groups. The chelator may be any chelatorknown in the art for complexing a medically useful metal ion orradionuclide. In some embodiments, the chelator comprises one, two,three, four, five, six, seven, eight, nine, or ten donor atoms and/orgroups. In embodiments where the chelator comprises more than one donoratom and/or group, the donor atoms/groups may be the same or different.The chelator may be monodentate, bidentate, tridentate, tetradentate,pentadentate, or more. Non-limiting examples of donor atoms/groupsinclude —OH, —O⁻, —COOR′, —COOR, —N(R′)₂, ═N⁻, —SR′, —S, —OPO₃ ⁻, or—OPO₃R′, wherein each R′ can be the same or different and is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl,arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,heteroalkyl, heterocyclyl, heterocyclylalkyl, each optionallysubstituted. In some cases, the chelator may be a macrocycle.Non-limiting examples of chelators are described in International PCTPublication No. WO2011/005322 and U.S. Pat. No. 6,511,648, each of whichis incorporated herein by reference for all purposes. In someembodiments, the chelator comprises diaminodithiol,mercaptoacetyltriglycine, monoaminomonoamide, picolylamine monoaceticacid, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,bis(thiosemicarbazone), propyleneamine oxime, ethylenediaminetetraaceticacid, or diethylenetriaminepentaacetic acid. In some embodiments, thechelator comprises a metal atom (e.g., Al), wherein an imaging moiety(e.g., ¹⁸F) associates with the metal atom.

In some cases, an imaging moiety associated with a chelator may befurther associated with one or more ancillary or co-ligands. “Ancillary”or “co-ligands” may be ligands which serve to complete the coordinationsphere of the imaging moiety together with the chelator. In someembodiments, the imaging moiety coordination sphere may comprise one ormore bonding atoms and/or groups from the chelators and optionally, oneor more ancillary and/or co-ligands. Ancillary or co-ligands useful inthe preparation of radiopharmaceuticals and in diagnostic kits usefulfor the preparation of said radiopharmaceuticals may be comprised of oneor more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium,and tellurium donor atoms. Conditions for effecting association of animaging moiety with a chelator will depend on the type of chelator beingused and are well known in the art.

Imaging Agent Precursors

In another aspect of the invention, imaging agent precursors useful inthe preparation of imaging agents as described herein are provided. Incertain embodiments, an imaging agent precursor comprises a leavinggroup (e.g., a sulfonate, halide) that can be replaced with anucleophile in a substitution reaction to form an imaging agent. Theimaging agent precursor may also include functional groups that areoptionally protected. In some embodiments, an imaging agent precursorhas a substantially similar structure as an imaging agent describedabove (e.g., a compound comprising at least one imaging moiety), exceptthat the imaging moiety or the substituent which includes the imagingmoiety instead includes a leaving group. In certain embodiments, animaging agent precursor has a substantially similar structure as animaging agent described above, except that the chelator group is not yetassociated with an imaging moiety.

As used herein, the term “leaving group” is given its ordinary meaningin the art of synthetic organic chemistry and refers to an atom or agroup capable of being displaced by a nucleophile. Examples of suitableleaving groups include, but are not limited to, halides (such aschloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl,haloformates, —NO₂, trialkylammonium, and aryliodonium salts. In someembodiments, the leaving group is a sulfonic acid ester. In someembodiments, the sulfonic acid ester comprises the formula —OSO₂R′wherein R′ is selected from the group consisting alkyl optionally,alkenyl optionally substituted, heteroalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, arylalkyloptionally substituted, and heterarylalkyl optionally substituted. Insome embodiments, R′ is substituted or unsubstituted C₁-C₆ alkyl. Insome embodiments, R′ is methyl. In some embodiments, R′ is —CF₃. In someembodiments, R′ is substituted or unsubstituted aryl. In someembodiments, R′ is substituted or unsubstituted phenyl. In someembodiments R′ is:

In some cases, the leaving group is toluenesulfonate (tosylate, Ts),methanesulfonate (mesylate, Ms), p-bromobenzenesulfonyl (brosylate, Bs),or trifluoromethanesulfonate (triflate, Tf). In some cases, the leavinggroup is a brosylate (p-bromobenzenesulfonyl). In some cases, theleaving group is a nosylate (2-nitrobenzenesulfonyl). In someembodiments, the leaving group is a sulfonate-containing group. In someembodiments, the leaving group is a tosylate group. The leaving groupmay also be a phosphineoxide (e.g., formed during a Mitsunobu reaction)or an internal leaving group such as an epoxide or cyclic sulfate.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein.

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, heterocyclyl, or aryl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R⁹ is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and leavinggroup,

provided that at least one leaving group is present in the compound; and

provided that when W is aryl, a) R³ is not halo, alkyl or haloalkyl, orb) at least one R⁶ is selected from the group consisting of alkynyloptionally substituted, alkenyl optionally substituted, alkylsubstituted with —CN, alkyl substituted with —C(═O)OR⁸, alkylsubstituted with —C(═O)R⁸, alkyl substituted with —N(R⁷)₂, —CN, —NO₂,—N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸, —C(═O)R⁸, —C(═O)N(R⁷)₂, and—N(R⁷)C(═O)R⁸.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, or heterocyclyl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

Q has the structure:

each Y and each X is independently selected from the group consisting ofC, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least one Y is not C orC(R⁶);

each

is independently a single or double bond.

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, unsubstitutedalkyl or alkyl optionally substituted with a moiety other than ahalogen, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, —CN, and —NO₂;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, or 5;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

each R⁴, R⁵, and R¹¹ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

q, and r are each independently 0, 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, —NO₂, haloalkyl,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), and —CH₂O;

each R⁴ and R⁵ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of consisting of N(R⁷), S, O,C(═O), C(═O)O, OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

p is 0, 1, 2, 3, or 4;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup; and

R¹² is selected from the group consisting of alkynyl optionallysubstituted, alkenyl optionally substituted, alkyl substituted with —CN,alkyl substituted with —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkylsubstituted with —N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)R⁸, —C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R⁸,

provided that at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

R²⁰ is selected from the group consisting of hydrogen, heteroalkyloptionally substituted, alkoxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —CN, and —NO₂;

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and a leaving group, or optionally any twoR²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and aleaving group;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and a leaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted; G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one leaving group is present in the compound.

In some embodiments, a compound is provided comprising the structure:

or a salt thereof, wherein:

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and a leaving group, or optionally any twoR²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and aleaving group;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and a leaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halo, and a leaving group;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

R²⁹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group; G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted, provided at least one K isalkenylene, or alkynylene;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one leaving group is present in the compound.

In each of the above compounds comprising Formula (XI), (XII), (XIII),(XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), each group and/orvariable may optionally be selected from the groups and/or variablesprovided above for the corresponding imaging agents having Formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), respectively,wherein each imaging moiety in the groups provided for a compoundcomprising Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X) is replaced with a leaving group.

The following description of R⁶ groups may be used in connection with acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).In some embodiments, for a compound of Formula (I), (II), (III), (IV),(V), (VI), (VII), or (VIII), all but one R⁶ is H. That is, all R⁶ are Hand one R⁶ is not H. In some cases, the one R⁶ which is not H issubstituted with the at least one leaving group. In some cases, the oneR⁶ which is not H is the at least one leaving group. In someembodiments, for a compound of Formula (I), (II), (III), (IV), (V),(VI), (VII), or (VIII), at least one R⁶ is alkyl optionally substituted,alkoxy optionally substituted, or alkoxyalkyl optionally substituted,each substituted with a leaving group. In some embodiments, for acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII),at least one R⁶ is —(CH₂)_(j)L_(G); wherein L_(G) is a leaving group andj is 1, 2, 3, 4, 5, or 6. In some cases, at least one R⁶ is—(CH₂)_(j)L_(G), —(CH₂)₂L_(G), —(CH₂)₃L_(G), —(CH₂)₄L_(G), —(CH₂)₅L_(G),—(CH₂)₆L_(G), —(CH₂)₇L_(G), —(CH₂)₈L_(G), —(CH₂)₉L_(G), or—(CH₂)₁₀L_(G). In some embodiments, at least one R⁶ is —O(CH₂)_(j)L_(G);wherein L_(G) is a leaving group and j is 1, 2, 3, 4, 5, or 6. In somecases, at least one R⁶ is —O(CH₂)₅L_(G), —O(CH₂)₆L_(G), —O(CH₂)₇L_(G),—O(CH₂)₈L_(G), —O(CH₂)₉L_(G), or —O(CH₂)₁₀L_(G). In some embodiments, atleast one R⁶ is —(CH₂)O(CH₂)_(j)L_(G); wherein L_(G) is a leaving groupand each j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, atleast one R⁶ is —(CH₂)O(CH₂)_(j)L_(G); wherein L_(G) is a leaving groupand each j is independently 1, 2, 3, 4, 5, or 6. In some cases, at leastone R⁶ is —CH₂O(CH₂)L_(G), —CH₂O(CH₂)₂L_(G), —CH₂(CH₂)₃L_(G),—CH₂O(CH₂)₄L_(G), —CH₂O(CH₂)₅L_(G), —CH₂O(CH₂)₆L_(G), —CH₂O(CH₂)₇L_(G),—CH₂O(CH₂)₈L_(G), —H₂O(CH₂)₉L_(G), or —H₂O(CH₂)₁₀L_(G). In someembodiments, at least one R⁶ is —C≡C—(CH₂)_(j)L_(G); wherein L_(G) is aleaving group and j is 1, 2, 3, 4, 5, or 6. In some embodiments, atleast one R⁶ is —[(CH₂)_(j)O]_(j)(CH₂)_(j)L_(G); wherein L_(G) is aleaving group and each j is independently 1, 2, 3, 4, 5, or 6. In someembodiments, at least one R⁶ is —O[(CH₂)O]_(j)(CH₂)_(j)L_(G); whereinL_(G) is a leaving group and each j is independently 1, 2, 3, 4, 5, or6. In some embodiments, at least one R⁶ is optionally substituted alkylsubstituted with a leaving group. In some embodiments, at least one R⁶is —C(═O)O(CH₂)_(j)L_(G); wherein L_(G) is a leaving group and j is 1,2, 3, 4, 5, or 6. In some embodiments, at least one R⁶ is—C(═O)(CH⁻²)_(j)L_(G); wherein L_(G) is a leaving group and j is 1, 2,3, 4, 5, or 6. In some embodiments, at least one R⁶ is—(CH₂)NH(CH₂)_(j)L_(G); wherein L_(G) is a leaving group and each j isindependently 1, 2, 3, 4, 5, or 6. In some embodiments, at least one R⁶is Si(R⁹)₂L_(G), wherein each R⁹ is alkyl optionally substituted andwherein L_(G) is a leaving group. In some embodiments, at least one R⁶is B(R^(9′))₂L_(G), wherein each R^(9′) is alkyl optionally substitutedand wherein L_(G) is a leaving group, or optionally, two R^(9′) jointogether to form a ring which is a portion of leaving, or optionally,one R^(9′) is absent, for example:

(e.g., wherein each R is alkyl or aryl), In some embodiments, at leastone R⁶ is selected from the group consisting of —C≡C—CH₂CH₂CH₂L_(G),—C≡C—CH₂CH₂L_(G), —C≡C—CH₂L_(G), —CH₂L_(G), —(CH₂)₂L_(G), —(CH₂)₃L_(G),—(CH₂)₄L_(G), —(CH₂)₅L_(G), —(CH₂)₆L_(G), —OCH₂L_(G), —O(CH₂)₂L_(G),—O(CH₂)₃L_(G), —O(CH₂)₄L_(G), —O(CH₂)₅L_(G), —O(CH₂)₆L_(G),—CH₂O(CH₂)₂L_(G), —CH(CH₃)O(CH₂)₂L_(G), —CH₂O(CH₂)₃L_(G),—CD₂O(CH₂)₂L_(G), —(CH₂)₂O(CH₂)₂L_(G), —CHBrC(CH₃)₂L_(G),—CHClC(CH₃)₂L_(G), —CHFC(CH₃)₂L_(G), —C(═O)OCH₂L_(G),—C(═O)O(CH₂)₂L_(G), —C(═O)O(CH₂)₃L_(G), —CH₂NH(CH₂)₂L_(G),—CH₂NHCH₂L_(G), —CH₂O(CH₂)₂O(CH₂)₂L_(G), —CH₂O(CH₂)₂O(CH₂)₃L_(G),—O(CH₂)₂O(CH₂)₂L_(G), —C(═O)(CH₂)₂L_(G), and —C(═O)(CH₂)₃L_(G). For acompound of Formula (XI) or (XII), each of the R⁶ groups describedherein may be combined with any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′),J, W, m, and n, or combinations thereof, as described herein. For acompound of Formula (XIII), each of the R⁶ groups described herein maybe combined with any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), Q, J, andn, or combinations thereof, as described herein. For a compound ofFormula (XIV), each of the R⁶ groups described herein may be combinedwith any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), J, m, and n, orcombinations thereof, as described herein. For a compound of Formula(XV) or (XVI), each of the R⁶ groups described herein may be combinedwith any R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), R11, J, Z, m, q, and r,or combinations thereof, as described herein. For a compound of Formula(XVII), each of the R⁶ groups described herein may be combined with anyR¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R^(9′), J, Z, n, and m, or combinationsthereof, as described herein. For a compound of Formula (XVIII), each ofthe R⁶ groups described herein may be combined with any R¹, R², R³, R⁴,R⁵, R⁷, R⁸, R⁹, R^(9′), R¹², J, p, and n, or combinations thereof, asdescribed herein.

The following description of R²² groups may be used in connection with acompound of Formula (XIX) or (XX). In some embodiments, R²² is a leavinggroup. In some embodiments, R²² is substituted with a leaving group. Insome embodiments, R²² is alkyl optionally substituted, alkoxy optionallysubstituted, or alkoxyalkyl optionally substituted, each substitutedwith a leaving group. In some embodiments, R²² is —Si(R⁹)₃ or—B(R^(9′))₃. In some embodiments, R²² is —(CH₂)_(j)L_(G); wherein L_(G)is a leaving group and j is 1, 2, 3, 4, 5, or 6. In some cases, R²² is—(CH₂)_(j)L_(G), —(CH₂)₂L_(G), —(CH₂)₃L_(G), —(CH₂)₄L_(G), —(CH₂)₅L_(G),—(CH₂)₆L_(G), —(CH₂)₇L_(G), —(CH₂)₈L_(G), —(CH₂)₉L_(G), or—(CH₂)₁₀L_(G). In some embodiments, R²² is —O(CH₂)_(j)L_(G); whereinL_(G) is a leaving group and j is 1, 2, 3, 4, 5, or 6. In some cases,R²² is —O(CH₂)_(j)L_(G), —O(CH₂)₂L_(G), —O(CH₂)₃L_(G), —O(CH₂)₄L_(G),—O(CH₂)₅L_(G), —O(CH₂)₆L_(G), —O(CH₂)₇L_(G), —O(CH₂)₈L_(G),—O(CH₂)₉L_(G), or —O(CH₂)₁₀L_(G). In some embodiments, R²² is—(CH₂)_(j)O(CH₂)_(j)L_(G); wherein L_(G) is a leaving group and each jis independently 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—(CH₂)O(CH₂)_(j)L_(G); wherein L_(G) is a leaving group and each j isindependently 1, 2, 3, 4, 5, or 6. In some cases, R²² is—CH₂O(CH₂)_(j)L_(G), —CH₂O(CH₂)₂L_(G), —CH₂O(CH₂)₃L_(G),—CH₂O(CH₂)₄L_(G), —CH₂O(CH₂)₅L_(G), —CH₂O(CH₂)₆L_(G), —CH₂O(CH₂)₇L_(G),—CH₂O(CH₂)₈L_(G), —H₂O(CH₂)₉L_(G), or —CH₂O(CH₂)₁₀L_(G). In someembodiments, R²² is —C≡C—(CH₂)_(j)L_(G); wherein L_(G) is a leavinggroup and j is 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—[(CH₂)_(j)O]_(j)(CH₂)_(j)L_(G); wherein L_(G) is a leaving group andeach j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—O[(CH₂)_(j)O]_(j)(CH₂)_(j)L_(G); wherein L_(G) is a leaving group andeach j is independently 1, 2, 3, 4, 5, or 6. In some embodiments, R²² isoptionally substituted alkyl substituted with a leaving group. In someembodiments, R²² is —C(═O)O(CH₂)_(j)L_(G); wherein L_(G) is a leavinggroup and j is 1, 2, 3, 4, 5, or 6. In some embodiments, R²² is—C(═O)(CH₂)_(j)L_(G); wherein L_(G) is a leaving group and j is 1, 2, 3,4, 5, or 6. In some embodiments, R²² is —(CH₂)NH(CH₂)_(j)L_(G); whereinL_(G) is a leaving group and each j is independently 1, 2, 3, 4, 5, or6. In some embodiments, R²² is Si(R⁹)₂L_(G), wherein each R⁹ is alkyloptionally substituted and wherein L_(G) is a leaving group. In someembodiments, R²² is B(R^(9′))₂L_(G), wherein each R^(9′) is alkyloptionally substituted and wherein L_(G) is a leaving group. In someembodiments, R²² is selected from the group consisting of—C≡C—CH₂CH₂CH₂L_(G), —C≡CH₂CH₂L_(G), —C≡C—CH₂L_(G), —H₂L_(G),—(CH₂)₂L_(G), —(CH₂)₃L_(G), —(CH₂)₄L_(G), —(CH₂)₅L_(G), —(CH₂)₆L_(G),—OCH₂L_(G), —O(CH₂)₂L_(G), —O(CH₂)₃L_(G), —O(CH₂)₄L_(G), —O(CH₂)₅L_(G),—O(CH₂)₆L_(G), —CH₂O(CH₂)₂L_(G), —CH(CH₃)O(CH₂)₂L_(G), —CH₂O(CH₂)₃L_(G),—CD₂O(CH₂)₂L_(G), —(CH₂)₂O(CH₂)₂L_(G), —CHBrC(CH₃)₂L_(G),—CHClC(CH₃)₂L_(G), —CHFC(CH₃)₂L_(G), —C(═O)OCH₂L_(G),—C(═O)O(CH₂)₂L_(G), —C(═O)O(CH₂)₃L_(G), —CH₂NH(CH₂)₂L_(G),—CH₂NHCH₂L_(G), —CH₂O(CH₂)₂O(CH₂)₂L_(G), —CH₂O(CH₂)₂O(CH₂)₃L_(G),—O(CH₂)₂O(CH₂)₂L_(G), —C(═O)(CH₂)₂L_(G), and —C(═O)(CH₂)₃L_(G). For acompound of Formula (XIX), each of the R²² groups described herein maybe combined with any R⁷, R⁸, R²⁰, R²¹, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, G,a, K, b, and c, or combinations thereof, as described herein. For acompound of Formula (XX), each of the R²² groups described herein may becombined with any R⁷, R⁸, R²¹, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, G, a,K, b, and c, or combinations thereof, as described herein.

As described in more detail herein, in some embodiments, a diagnostickit is provided comprising one or more vials containing a compound asdescribed in this section or a salt thereof (e.g., a compound comprisingFormula (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX),or (XX)), and optionally other components. In some embodiments, thediagnostic kit is for the preparation of diagnostic agents for imaging,detecting, and/or monitoring myocardial perfusion in a subject. In someembodiments, said other components are selected from the groupconsisting of ancillary ligands, reducing agents, transfer ligands,buffers, lyophilization aids, stabilization aids, solubilization aids,and bacteriostats.

As described in more detail herein, in some embodiments, methods forforming an imaging agent are provided, the method comprising reacting acompound as described in this section or a salt thereof (e.g., acompound comprising Formula (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), (XVIII), (XIX), or (XX)) with an ¹⁸F-containing species toproduce an imaging agent comprising ¹⁸F (e.g., a compound comprisingFormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X,respectively).

Salts

In some embodiments, the imaging agents and precursors described hereinmay be salts. In some cases, the salt is a pharmaceutically acceptablesalt. However, in the case of imaging agent precursors, the salt may notnecessarily be a pharmaceutically acceptable salt. Those of ordinaryskill in the art will be aware of suitable counter anions for forming asalt of the imaging agents and imaging agent precursors describedherein. In addition, those of ordinary skill in the art will be awarethat the counter anion X^(⊖) may have a charge of less than −1 (e.g.,−2, −3), and in such embodiments, each counter anion X^(⊖) may beassociated with more than one molecule of the compound. In someembodiments, the counter ion is a halide, phosphate, hydrogen phosphate,dihydrogen phosphate, hydrogen sulfate, sulfate, trifluoroacetate,toluenesulfonate, acetate, formate, citrate, ascorbate, mesylate(methanesulfonate), triflate (trifluoromethanesulfonate), tartrate,lactate, or benzoate. Additional non-limiting examples of suitablecounter anions include the conjugate base of inorganic acids (e.g.,chloride, bromide, iodide, fluoride, nitrate, sulfate, phosphate) orfrom the conjugate base of organic acids (e.g., carboxylate, acetate,benzoate, tartrate, adipate, lactate, formate, maleate, glutamate,ascorbate, citrate, gluconate, oxalate, succinate, pamoate, salicylate,isethionate, succinamate, mono-diglycollate, di-isobutyrate,glucoheptonate). Still yet other non-limiting examples of salts includeadipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline,aspartate, bisulfate, camphorate, digluconate, dihydrobromide,disuccinate, glycerophosphate, hemisulfate, fluoride, iodide,methylenebis(salicylate), napadisylate, oxalate, pectinate, persulfate,phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate,undecanoate, acetate, benzenesulfonate, benzoate, bicarbonate,bitartrate, bromide, calcium edentate, camyslate, carbonate, chloride,citrate, dihydrochloride, edentate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, bromide, chloride, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, andtriethiodide (see Berge et al., Journal of Pharmaceutical Sciences,66(1), 1977, 1-19).

Methods of Synthesizing Imaging Agents

In other aspects, methods are provided for synthesizing imaging agents.The methods described herein may be used for the synthesis of a varietyof imaging agents as described herein from imaging agent precursors asdescribed herein. Generally, an imaging agent may be synthesized byreacting an imaging agent precursor with a reactant comprising theimaging moiety. In some cases, the reaction involves the formation of acovalent bond between the imaging agent precursor and the imaging moietyof the reactant. In other cases, however, the reaction involvesnon-covalent association of an imaging moiety with an imaging agentprecursor (e.g., via chelation). The following sections provide a numberof non-limiting embodiments for forming an imaging agent from an imagingagent precursor. Those of ordinary skill in the art will be aware ofother suitable methods and techniques for forming an imaging agent froman imaging agent precursor. In addition, other steps which may beconducted in connection with the synthesis of an imaging agent (e.g.,formulation, purification) are also described.

In some cases, the imaging agent is formed by reacting an imaging agentprecursor with an imaging moiety. In certain embodiments, a methodinvolves reacting an imaging agent precursor comprising a leaving groupwith a source of an imaging moiety (e.g., a fluoride species). Forexample, the imaging moiety replaces the leaving group via asubstitution reaction, such as an S_(N)2 or S_(N)1 reaction. That is,during the reaction an imaging moiety replaces the leaving group,thereby producing the imaging agent.

The methods described herein may be used for the synthesis of a widevariety of imaging agents from an imaging agent precursor. Generally,the imaging agent precursor may include at least one leaving group thatmay be displaced by an imaging moiety, such as an ¹⁸F species. Imagingagent precursors may be synthesized using methods known to those ofordinary skill in the art.

A. General Reaction Conditions

The synthetic methods described herein may be carried out in anysuitable solvent, including, but not limited to, non-halogenatedhydrocarbon solvents (e.g., pentane, hexane, heptane, cyclohexane),halogenated hydrocarbon solvents (e.g., dichloromethane, chloroform,fluorobenzene, trifluoromethylbenzene), aromatic hydrocarbon solvents(e.g., toluene, benzene, xylene), ester solvents (e.g., ethyl acetate),ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane.), and alcohol solvents (e.g., ethanol, methanol,propanol, isopropanol, tert-butanol). In certain embodiments, a proticsolvent is used. In other embodiments, an aprotic solvent is used.Non-limiting examples of solvents useful in the synthetic methodsinclude acetone, acetic acid, formic acid, dimethyl sulfoxide, dimethylformamide, acetonitrile, p-cresol, glycol, petroleum ether, carbontetrachloride, hexamethylphosphoric triamide, triethylamine, picoline,and pyridine.

The methods may be carried out at any suitable temperature. In somecases, the method is carried out at about room temperature (e.g., about20° C., between about 20° C. and about 25° C., about 25° C., or thelike). In some cases, however, the method is carried out at atemperature below or above room temperature, for example, at about −78°C. at about −70° C., about −50° C., about −30° C., about −10° C., about−0° C., about 10° C., about 30° C., about 40° C., about 50° C., about60° C., about 70° C., about 80° C., about 90° C., about 100° C., about120° C., about 140° C., or the like. In some embodiments, the method iscarried out at temperatures above room temperature, for example, betweenabout 25° C. and about 120° C., or between about 25° C. and about 100°C., or between about 40° C. and about 120° C., or between about 80° C.and about 120° C. The temperature may be maintained by reflux of thesolution. In some cases, the method is carried out at temperaturesbetween about −78° C. and about 25° C., or between about 0° C. and about25° C.

The methods described herein may be carried out at any suitable pH, forexample, equal to or less than about 13, equal to or less than about 12,equal to or less than about 11, equal to or less than about 10, equal toor less than about 9, equal to or less than about 8, equal to or lessthan about 7, or equal to or less than about 6. In some cases, the pHmay be greater than or equal to 1, greater than or equal to 2, greaterthan or equal to 3, greater than or equal to 4, greater than or equal to5, greater than or equal to 6, greater than or equal to 7, or greaterthan or equal to 8. In some cases, the pH may be between about 2 andabout 12, or between about 3 and about 11, or between about 4 and about10, or between about 5 and about 9, or between about 6 and about 8, orabout 7.

The percent yield of a product may be greater than about 60%, greaterthan about 70%, greater than about 75%, greater than about 80%, greaterthan about 85%, greater than about 90%, greater than about 92%, greaterthan about 95%, greater than about 96%, greater than about 97%, greaterthan about 98%, greater than about 99%, or greater.

B1. Halogenation

In some embodiments, an imaging agent is formed by reacting an imagingagent precursor with an imaging moiety. In certain embodiments, animaging agent precursor comprises at least one leaving group that issusceptible to being displaced by an imaging moiety, such as, forexample, a halogen (e.g., ¹⁸F, ⁷⁶Br, ¹²⁴I, ¹³¹I). Thus, in certainembodiments, the methods described herein involve reacting an imagingagent precursor comprising a leaving group with a source of an imagingmoiety.

In some embodiments, a halide displaces a leaving group on a providedimaging agent precursor via a substitution reaction, such as an S_(N)2or S_(N)1 reaction, thereby producing an imaging agent. For example, ahalide such as fluoride may displace a sulfonate leaving group of theimaging agent precursor to yield a fluorinated imaging agent. In certainembodiments, a substitution reaction is a one-step procedure which doesnot require a subsequent deprotection step. That is, the substitutionstep is performed on a fully deprotected imaging agent precursor. Incertain embodiments, a substitution reaction provided by the presentinvention produces a fluorinated imaging agent (e.g., an imaging agentcomprising ¹⁸F).

In some embodiments, a provided imaging agent is synthesized via an arylor heteroaryl halogenation reaction (e.g., aryl fluorination, arylbromination, aryl iodination). Many techniques for synthesizing aryl orheteroaryl halides are known in the art. For example, in certainembodiments, an imaging agent comprising an ¹²⁴I, ¹³¹I, or ⁷⁶Br imagingmoiety is synthesized via a Sandmeyer reaction from an aryl diazoniumimaging agent precursor, with or without the use of copper(I) catalysis(see, for example, Beletskaya et al., Synthesis, 2007, 2534-2538;Hubbard et al., J. Org. Chem., 2008, 73, 316-319; Filimonov et al., Org.Lett., 2008, 10, 3961-3964; Krasnokutskaya et al., Synthesis, 2007,81-84). In other embodiments, an imaging agent comprising an ¹⁸F imagingmoiety is synthesized via a related Balz-Schiemann reaction from adiazonium imaging agent precursor. In certain embodiments, an imagingagent comprising a ¹²⁴I or ¹³¹I imaging moiety is synthesized via an“aromatic Finkelstein” reaction from an aryl bromide imaging agentprecursor (see, for example, A. Klapars, S. L. Buchwald, J. Am. Chem.Soc., 2002, 124, 14844-14845). In other embodiments, an imaging agentcomprising an ¹²⁴I, ¹³¹I, or ⁷⁶Br imaging moiety is synthesized byallowing a boronic acid or ester imaging agent precursor to react withthe appropriate N-halosuccinimide reagent (Thiebes et al., Synlett,1998, 141-142) or copper bromide reagent (see, for example, Murphy etal., J. Am. Chem. Soc., 2007, 129, 15434-15435; Thompson et al.,Synthesis, 2005, 547-550). In some embodiments, an imaging agentcomprising a ⁷⁶Br imaging moiety is synthesized via anorganotrifluoroborate imaging agent precursor (see, for example, G. W.Kabalka, A. R. Mereddy, Organometallics, 2004, 23, 4519-4521). One ofordinary skill in the art will appreciate that there are many otherconditions under which activated or deactivated arenes may behalogenated (see, for example, Kraszkiewicz et al., Synthesis, 2006,1195-1199; Ganguly et al., Synthesis, 2010, 1467-1472; Iskra et al.,Synthesis, 2004, 1869-1873; Castanet et al., Tetrahedron Lett., 2002,43, 5047-5048; Prakash et al., J. Am. Chem. Soc., 2004, 126,15570-15776; Lulinski et al., Synthesis, 2004, 441-445; Ganguly et al.,Synthesis, 2005, 1103-1108; Rajesh et al., Org. Chem., 2007, 72,5867-5869; Kumar et al., Synthesis, 2010, 1629-1632; Zhou et al.,Synthesis, 2011, 207-209; Menzel et al., J. Org. Chem., 2006, 71,2188-2191), and such a reaction may be employed in certain embodimentsto synthesize imaging agents described herein. One of ordinary skill inthe art will also appreciate that many of the aryl halogenationreactions described herein will also be effective for generating ahaloalkene- or haloalkyne-containing imaging agent, as well ashaloheteroaryl-containing imaging agents.

In some embodiments, an imaging agent comprising an ¹⁸F imaging moietyis synthesized via an aryl fluorination. See, for example, Furuya etal., Synthesis, 2010(11): 1804-1821 (2010), for an informative review ofaryl fluorination reactions. For example, in certain embodiments, animaging agent comprising an ¹⁸F imaging moiety is synthesized via anucleophilic fluorination reaction. Examples of nucleophilicfluorination reactions include, but are not limited to, the Halexprocess (Adams et al., Chem Soc Rev 1999; 28:225; Horwitz et al., J.Org. Chem 1961; 26:3392; Barlin et al., J. Chem. Soc., Perkin Trans 11972:1269; Pike et al., J. Chem. Soc., Chem Commun 1995:2215; Shah etal., J. Chem. Soc., Perkin Trans 1 1998:2043; Ermert et al., J LabelledCompd Radiopharm 2004; 47:429), fluorodenitration (Adams et al., ChemSoc Rev 1999; 28:225; Adams et al., J. Fluorine Chem 1998; 92:127),displacement of ammonium with fluoride (Angelini et al., J. FluorineChem 1985; 27:177), and fluorination of diaryliodonium salts (Zhdankinet al., Chem Rev 2008; 108:5299; Beringer et al., J. Am. Chem Soc 1953;75:2708; Ross et al., J. Am. Chem Soc 2007; 129:8018). Trialkylammoniumfluoride reagents may also be employed in nucleophilic fluorinationreactions (Sun et al., Angew. Chem., Int. Ed 2006; 45:2720; Grushin etal., Organometallics 2008; 27:4825). In certain embodiments, anucleophilic fluorination reaction is Palladium catalyzed (see, forexample, Grushin et al., Organometallics 2008; 27:4825; Watson et al.,Science 2009; 325:1661). In other embodiments, an imaging agentcomprising an ¹⁸F imaging moiety is synthesized via an electrophilicfluorination reaction. Examples of electrophilic fluorination reactionsinclude, but are not limited to, fluorination of aryl Grignard reagents(Anbarasan P, Neumann H, Beller M. Angew Chem, Int Ed. 2010; 49:2219),fluorination of arylmagnesium reagents (Yamada S, Gavryushin A, KnochelP. Angew Chem, Int Ed. 2010; 49:2215), fluorination of organometallicreagents such as arylzinc halides, arylsilanes, arylstannanes,arylgermaniums, arylboronic ester, or arylboronic acids (Bryce et al.,J. Chem. Soc, Chem Commun 1986:1623; Tius et al., Synth Commun 1992;22:1461; Cazorla et al., Tetrahedron Lett 2009; 50:3936), fluorinationof arylsilanes (Lothian et al., Synlett 1993:753), andfluorodestannylation reactions (Lothian et al., Synlett 1993:753;Namavari et al., Appl Radiat Isot 1992; 43:989.). In some embodiments,an electrophilic fluorination reaction employs stoichiometric orcatalytic palladium (see, for example, Furuya et al., Angew Chem, Int Ed2008; 47:5993) or silver (see, for example, Furuya et al., J. Am. ChemSoc 2009; 131:1662; Furuya et al., Org Lett 2009; 11:2860).

B2. Fluorination

It should be understood, that while the following section focuses onfluorination reactions, this is by no means limiting, and the teachingsof this section may be applied to other halogenation reactions.

In some embodiments, a method for synthesizing an imaging agentcomprises contacting an imaging agent precursor of the invention with afluoride species resulting in the fluoride species replacing the leavinggroup of the precursor to produce an imaging agent. In some embodiments,an inventive method employs a reaction described herein, such as in thedescription of halogenation reactions above.

In certain embodiments, a method for synthesizing an imaging agentinvolves a nucleophilic fluorination reaction. It will be understoodthat the discussion of nucleophilic fluorination is exemplary of themethods described herein and is not limiting. In certain embodiments, animaging agent precursor comprising a leaving group is reacted in thepresence of a fluoride species, whereby S_(N)2 or S_(N)1 displacement ofthe leaving group by the fluoride species produces an imaging agent. Insome embodiments, for a composition, a fluoride species is isotopicallyenriched with ¹⁸F.

Those of ordinary skill in the art will be aware of suitable conditionsfor fluorinating a compound. For example, see International PatentApplication PCT/US2011/024109, filed Feb. 8, 2011, to Cesati et al., andIntenational Patent Application No. PCT/US2005/004687, filed Feb. 11,2005, to Casebier et al., each incorporated by reference herein for allpurposes. In some cases, the source of fluorine is a fluoride salt(e.g., KF, NaF, tetralkylammonium fluoride).

In some embodiments, a fluorinating agent for use in a provided methodis a source of fluoride. In certain embodiments, a fluorinating agentfor use in a provided method is NaF or KF. In certain embodiments, afluorinating agent for use in a provided method is isotopically enrichedwith ¹⁸F. In certain embodiments, suitable conditions for a fluorinationreaction according to the present invention comprise the presence of anammonium salt or a bicarbonate salt.

The fluorine source may comprise or be associated with or may be used inconnection with another reagent. In some embodiments, an additionalreagent may be capable of enhancing the reactivity of the fluorinespecies or otherwise facilitating conversion of the precursor to theimaging agent. For example, in certain embodiments, an additionalreagent is used in combination with a multidentate ligand, such as acrown ether or a cryptand that is capable of chelating a metal ion. Incertain embodiments, a multidentate ligand is, for example,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (i.e.,Kryptofix®222). In certain embodiments, when KF is a fluorine source,cryptands having a high affinity for potassium are useful as theychelate potassium and thereby increase the reactivity of the fluorideion. In some embodiments, cryptands having an affinity for potassiumnear that of Kryptofix® 222 (e.g., 75%, 80%, 85%, 90%, 95%, or more ofthe Kryptofix® 222's affinity for potassium) are used. The reactionconditions may comprise one or more solvents.

In some embodiments, the fluorination occurs in the presence of K₂CO₃and Kryptofix® 222 (or any another cryptand having affinity for thecation of interest, including for example potassium, near that ofKryptofix® 222) in MeCN (acetonitrile) alone or in combination withanother solvent. In some embodiments, the molar ratio of K₂CO₃ toimaging agent precursor ranges from about 0.25:1 to about 5:1, forexample 0.5:1 to 1:1.

In some embodiments, fluorination occurs in the presence oftetraalkylammonium carbonate or tetraalkylammonium bicarbonate in MeCNas the solvent. In some embodiments, the molar ratio oftetraalkylammonium carbonate or bicarbonate to imaging agent precursoris less than about 2:1. Other molar ratios are provided herein.

In certain embodiments, the synthetic methods described herein involve asingle-step preparation of imaging agents of the invention. In certainembodiments, a single-step method involves fluorination of a precursorin the presence of, for example, K₂CO₃/Kryptofix® 222 (or other suitablealternatives to Kryptofix® 222) or tetraalkylammonium carbonate orbicarbonate (e.g., in MeCN alone or in an MeCN mixture).

In certain embodiments, single-step preparation methods are particularlysuitable when particular salt forms of the imaging agent precursors ofthe invention are used, such as halide, acetate, formate, citric,ascorbate, trifluoroacetate, tolunesulfonate, benzoate, acetate,phosphate, sulfate, tosylate, and mesylate.

In some embodiments, one or more reagents are used in a reaction mixturecomprising an imaging agent precursor and a fluoride species. A“reagent,” also referred to as an “additive,” is used herein to mean anychemical compound added to a reaction mixture. A reagent may be consumedor not consumed during the reaction. A reagent may be a stoichiometricor catalytic reagent. Exemplary reagents include catalysts, salts,oxidants, reductants, chelating agents, bases, acids, metals, phasetransfer reagents, and others as would be appreciated by one of skill inthe art.

A reagent may, in some embodiments, facilitate reaction between animaging agent precursor and a fluoride species and/or may aid instabilizing a resultant imaging agent. For example, in certainembodiments, a fluoride species may have relatively low reactivity(e.g., nucleophilicity), and addition of certain reagents may enhancethe reactivity of the fluoride species. As an illustrative embodiment, afluorine species may be a negatively charged fluoride ion (e.g., anisotopically enriched ¹⁸F ion), and a reagent may be used to bind to anypositively charged counter ions present within the reaction mixture,thereby enhancing the reactivity of the fluoride ion. An example of sucha reagent is a cryptand such as, but not limited to, Kryptofix® (e.g.,Kryptofix® 222). In some embodiments, a reagent decreases the rate ofundesired side reactions.

In some embodiments, a reagent may be combined with a fluoride speciesprior to its contact with an imaging agent precursor. For example, incertain embodiments, a solution comprising a fluoride species and areagent is prepared, and the solution is added to an imaging agentprecursor. In other embodiments, a solid comprising a fluoride speciesand a reagent is prepared, and the solid is contacted with an imagingagent precursor in solution. In certain embodiments, a fluoride speciesis adsorbed onto a solid support (e.g., an anion exchange column), and asolution comprising the reagent is used to elute the fluoride speciesfrom the solid support. The eluted solution is then contacted with theimaging agent precursor, or is concentrated to produce a solid, which isthen contacted with the imaging agent precursor in solution.

In some embodiments, a provided reagent is a bicarbonate salt. As usedherein, the term “bicarbonate salt” refers to a salt comprising abicarbonate or hydrogen carbonate ion (HCO₃ ⁻ ion). In some embodiments,a bicarbonate salt is a metal bicarbonate, such as sodium bicarbonate,calcium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.In certain embodiments, a bicarbonate salt is potassium bicarbonate(KHCO₃). In some embodiments, a bicarbonate salt comprises a non-metalcounter ion, such as ammonium bicarbonate. For example, a bicarbonatesalt may be a tetraalkylammonium bicarbonate salt having the formula,R₄NHCO₃, wherein R is alkyl. In some embodiments, R may be lower alkyl,such as methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like. Incertain embodiments, the ammonium salt is Et₄NHCO₃. In otherembodiments, the salt is Me₄NHCO₃, i-Pr₄NHCO₃, n-Pr₄NHCO₃, n-Bu₄NHCO₃,i-Bu₄NHCO₃, or t-Bu₄NHCO₃.

In some embodiments, a provided reagent is a carbonate salt. As usedherein, the term “carbonate salt” refers to a salt comprising acarbonate ion (CO₃ ⁻² ion). In some embodiments, a carbonate salt is ametal carbonate, such as sodium carbonate, calcium carbonate, potassiumcarbonate, and magnesium carbonate. In certain embodiments, a carbonatesalt is potassium carbonate (K₂CO₃). In some embodiments, a carbonatesalt comprises a non-metal counter ion, such as ammonium carbonate. Forexample, a carbonate salt may be a tetraalkylammonium carbonate salthaving the formula, (R₄N)₂CO₃, wherein R is alkyl. In some embodiments,R may be a lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl,hexyl, or the like. In certain embodiments, the ammonium salt is(Et₄N)₂CO₃. In other embodiments, the salt is (Me₄N)₂CO₃, (i-Pr₄N)₂CO₃,(n-Pr₄N)₂CO₃, (n-Bu₄N)₂CO₃, (i-Bu₄N)₂CO₃, or (t-Bu₄N)₂CO₃.

Without wishing to be bound by any particular theory, use ofbicarbonate, carbonate, and/or ammonium salt(s) may aid in decreasingthe rate of competing reactions such as hydrolysis during nucleophilicfluorination of an imaging agent precursor.

In some embodiments, a reagent is a salt comprising a cation that formsa weakly coordinating salt with a fluoride species. As used herein, a“cation that forms a weakly coordinating salt with a fluoride species”refers to a cation that renders a fluoride species reactive in thecontext of a fluorination reaction. For example, a cation may notstrongly bind to the fluoride species, allowing the fluoride species toact as a nucleophile during a nucleophilic fluorination reaction. Thoseof ordinary skill the art would be able to select an appropriate cationthat would be suitable as a weakly coordinating counter ion for afluoride species. For example, a cation may be have a relatively largeatomic radius and/or may be a weak Lewis base. In some cases, a cationmay be selected to be lipophilic. In some cases, a cation may compriseone or more alkyl groups. Examples of weakly coordinating cationsinclude cesium ions, ammonium ions, weakly coordinating salts ofhexamethylpiperidindium, S(NMe₂)₃, P(NMe₂)₄, tetraaalkylphosphoniumsalts, tetraarylphosphonium salts, (e.g., tetraphenylphosphonium),hexakis(dimethylamino)diphosphazenium, and tris(dimethylamino)sulfonium.

In some embodiments, a provided reagent is an ammonium salt, i.e., asalt comprising a substituted or unsubstituted ammonium ion. In someembodiments, an ammonium ion is a weakly coordinating cation. In someembodiments, an ammonium salt has the formula, R₄NX, where each R can bethe same or different and is alkyl, heteroalkyl, aryl, heteroaryl, orheterocyclic, each optionally substituted, and X is a negatively chargedcounter ion. In some cases, R is alkyl, heteroalkyl, aryl, heteroaryl,or heterocyclic, each optionally substituted. In some embodiments,ammonium salt may include a range of negatively charged counter ions,including halides, carbonates, and bicarbonates. Examples of ammoniumsalts include, but are not limited to, ammonium bicarbonate salts,ammonium hydroxide salts, ammonium acetate salts, ammonium lactatesalts, ammonium trifluoroacetate salts, ammonium methanesulfonate salts,ammonium p-toluenesulfonate salts, ammonium nitrate salts, ammoniumhalide salts (e.g., ammonium iodide salts), and ammonium bisulfatesalts.

In one set of embodiments, an ammonium salt is a tetraalkylammoniumsalt, such as a tetraalkylammonium bicarbonate salt. For example, anammonium salt may have the formula, R₄NHCO₃, wherein each R isindependently alkyl. In some cases, R is optionally substituted. In someembodiments, the alkyl group is a lower C₁-C₆ alkyl group. In someembodiments, an tetraalkylammonium salt is a basic tetraalkylammoniumsalt.

In some embodiments, a salt (e.g., bicarbonate salt and/or ammoniumsalt) may be utilized in the reaction such that the molar ratio of thesalt to the imaging agent precursor is less than or equal to about 2:1.In some cases, the molar ratio is less than or equal to about 2:1, lessthan or equal to about 1.9:1, less than or equal to about 1.8:1, lessthan or equal to about 1.7:1, less than or equal to about 1.6:1, lessthan or equal to about 1.5:1, less than or equal to about 1.4:1, or lessthan or equal to about 1.3:1, or less than or equal to about 1.25:1, orless than or equal to about 1.2:1, or less than or equal to about 1.1:1,or less than or equal to about 1:1, or less than or equal to about0.75:1, or less than or equal to about 0.5:1, or less than or equal toabout 0.25:1, or less than or equal to about 0.1:1, or less than orequal to about 0.05:1. In some cases, the ratio is greater than about0.05:1, greater than about 0.01:1, or greater than about 0.25:1. In someembodiments, the molar ratio of salt additive to imaging agent precursoris between about 0.5:1 to about 1:1, or about 0.25:1 to about 1:1, orabout 0.25:1 to about 0.75:1, about 1.49:1 to about 0.05:1, or betweenabout 1.4:1 to about 0.25:1, or between about 0.25:1 and about 1.4:1, orbetween about 0.25:1 and about 1.25:1.

In some embodiments, a reagent is used in combination with a speciescapable of enhancing the reactivity of the fluoride species or otherwisefacilitating conversion of the imaging agent precursor to the imagingagent. For example, a species may be a compound capable of chelating oneor more ions (e.g., metal ions) that may be present within the reactionmixture. Without wishing to be bound by theory, a species may be used tochelate a counter ion to a fluoride species, such as a potassium ion,thereby increasing the reactivity (e.g., nucleophilicity) of thefluoride species. In certain embodiments, a reagent is used incombination with a multidentate ligand, such as a crown ether or acryptand that is capable of chelating a metal ion. The multidentateligand (e.g., cryptand) may be selected based on the metal ion to bechelated. A multidentate ligand may be, for example,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (e.g.,Kryptofix® 222). Other cryptands will be known to those of ordinaryskill in the art. Some embodiments involve use of a carbonate salt incombination with4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane. In aspecific embodiment, K₂CO₃ and/or KHCO₃ is used in combination with4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane.

In another set of embodiments, it may be advantageous to utilize themethods described herein in the absence of a cryptand. The term“cryptand” is given its ordinary meaning in the art and refers to a bi-or a polycyclic multidentate ligand for a cation. For example, inventivemethods may be carried out using an ammonium salt, in the absence of acryptand (e.g.,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane). In someembodiments, cryptands may increase the pH of the reaction solution,which in the presence of another reagent (e.g., carbonate salt) mayadversely affect the yield and/or purity of the fluorination reaction.Accordingly, in certain embodiments, carrying out the fluorinationreaction, in the absence of a cryptand, and optionally in the presenceof another reagent (e.g., ammonium and/or bicarbonate salt) may increasethe yield and/or purity of the reaction.

In another set of embodiments, a method according to the presentinvention is performed in the absence of a carbonate salt.

Those of ordinary skill in the art will be able to select and/ordetermine an appropriate set of reaction conditions (e.g.,concentration, temperature, pressure, reaction time, solvents) suitablefor use in a particular application. In some embodiments, an imagingagent may be further processed using one or more purificationtechniques, and may optionally be combined with additional components,such as a stabilizing agent.

In some embodiments, an imaging agent is formed as a salt (e.g., apharmaceutically acceptable salt). Pharmaceutically acceptableexcipients and other aspects of pharmaceutically acceptable compositionsare described herein.

Those of ordinary skill in the art would be able to select a source of afluoride species suitable for use in the methods described herein. Theterm “fluoride species” as used herein refers to a fluoride atom orgroup of atoms comprising at least one fluoride atom, wherein thefluoride atom is capable of reacting with another compound (e.g., animaging agent precursor). In some embodiments, an isotopically-enriched¹⁸F species may be produced by the nuclear reaction ¹⁸O (p,n)¹⁸F fromproton bombardment of [¹⁸O]H₂O in a cyclotron. In certain embodiments, amethod may involve treating a solution of the ¹⁸F species to remove anyimpurities, such as unreacted [¹⁸O]H₂O. For example, a solution of the¹⁸F species may be filtered through an anion exchange column, where the¹⁸F species is retained on the cationic resin matrix while the [¹⁸O]H₂Ois eluted. The ¹⁸F species is then removed by washing the anion exchangecolumn with various mixtures of solvents and optional reagents (e.g.,salt), forming an ¹⁸F-containing solution. In some embodiments, an anionexchange column is washed with an aqueous solution of a salt, such asK₂CO₃ or Et₄NHCO₃. In other embodiments, a column is washed (e.g., withaqueous K₂CO₃), and the resulting solution diluted (e.g., with MeCN)and/or concentrated (e.g., to dryness using elevated temperature and/orreduced pressure). Anhydrous [¹⁸F]KF and/or [¹⁸F]Et₄NF may be obtainedand reacted with a compound or a salt thereof.

In some embodiments, a ¹⁸F-containing solution is combined withadditional components prior to reaction with an imaging agent precursor.For example, one or more solvents may be added to dilute a¹⁸F-containing solution to a desired concentration. In certainembodiments, a ¹⁸F-containing solution is diluted with acetonitrile(MeCN). In certain embodiments, a ¹⁸F-containing solution is dilutedwith acetonitrile (MeCN) and t-BuOH.

In some embodiments, a ¹⁸F-containing solution may be concentrated todryness by exposure to elevated temperature and/or reduced pressure toform an anhydrous ¹⁸F-containing solid. In some embodiments, a¹⁸F-containing solid may further comprise one or more reagents (e.g.,salts). The chemical composition of a ¹⁸F-containing solid may depend onthe number and kind of reagents used in preparation of the¹⁸F-containing solution. For example, a solution of potassium carbonatemay be used to elute a ¹⁸F species from the anion exchange column,thereby resulting in an ¹⁸F-containing solid comprising [¹⁸F]KF. Inanother example, a solution of tetraethylammonium bicarbonate is used toelute a ¹⁸F species from the anion exchange column, thereby resulting inan ¹⁸F-containing solid comprising [¹⁸F]Et₄NF.

In some embodiments, a solution comprising a ¹⁸F species is heated to atemperature ranging from room temperature to about 200° C. For example,a solution comprising a [¹⁸F]-fluoride may be heated to elevatedtemperatures to encourage evaporation of the solvent (e.g., to about110° C.). In some embodiments, a solution is heated to a temperatureranging from about 90-120° C. or from about 100-150° C. In someembodiments, a solution is heated to about 75° C., about 85° C., about95° C., about 105° C., about 115° C., about 125° C., or greater. In someembodiments, a solution is placed under a reduced pressure of about 100mm Hg, about 125 mm Hg, about 150 mm Hg, about 175 mm Hg, about 200 mmHg, about 225 mm Hg, about 250 mm Hg, about 275 mm Hg, about 300 mm Hg,about 325 mm Hg, about 350 mm Hg, about 375 mm Hg, about 400 mm Hg, orgreater. In some embodiments, a solution is placed under a reducedpressure of about 100 mbar, about 125 mbar, about 150 mbar, about 175mbar, about 200 mbar, about 225 mbar, about 250 mbar, about 275 mbar,about 280 mbar, about 300 mbar, about 325 mbar, about 350 mbar, about375 mbar, about 400 mbar, about 450 mbar, about 500 mbar, or greater.Those of ordinary skill in the art would be able to select and/ordetermine conditions suitable for a particular process. In someembodiments, a solution is concentrated to dryness at about 150 mm Hgand about 115° C. In some embodiments, a solution is concentrated todryness at about 375 mm Hg and about 115° C. In some embodiments, asolution is concentrated to dryness at about 400 mbar and about 110-150°C. In some embodiments, a solution is concentrated to dryness at about280 mbar and about 95-115° C.

In certain embodiments, a fluoride species and/or a reagent, if present,is then contacted with an imaging agent precursor under conditions thatresult in conversion of the imaging agent precursor to the imaging agentproduct via nucleophilic fluorination. Those of ordinary skill in theart would be able to select conditions suitable for use in a particularreaction. For example, in certain embodiments, the ratio of fluoridespecies to imaging agent precursor may be selected to be about 1:10,000or more, about 1:5000 or more, about 1:3000 or more, about 1:2000 ormore, about 1:1000 or more, about 1:500 or more, about 1:100 or more,about 1:50 or more, about 1:10 or more, about 1:5 or more, or, in somecases, about 1:1 or more. In some embodiments, a fluoride species may bepresent at about 10 mol %, or about 5 mol %, or about 3 mol %, or about2 mol %, or about 1 mol % or about 0.5 mol %, or about 0.1 mol %, orabout 0.05 mol %, or about 0.01 mol % relative to the amount of imagingagent precursor. In some embodiments, a fluoride species is isotopicallyenriched with ¹⁸F. For example, in some embodiments, the ratio of ¹⁸Fspecies to imaging agent precursor may be selected to be about1:1,000,000 or more, or about 1:500,000 or more, or about 1:250,000 ormore, or about 1:100,000 or more, or about 1:50,000 or more, or about1:25,000 or more, or about 1:10,000 or more, about 1:5000 or more, about1:3000 or more, about 1:2000 or more, about 1:1000 or more, about 1:500or more, about 1:100 or more, about 1:50 or more, about 1:10 or more,about 1:5 or more, or, in some cases, about 1:1 or more.

In some embodiments, a nucleophilic fluorination reaction is carried outin the presence of one or more solvents, for example, an organicsolvent, a non-organic solvent (e.g., an aqueous solvent), or acombination thereof. In some embodiments, the solvent is a polar solventor a non-polar solvent. In some embodiments, the solvent is an aqueoussolution, such as water. In some embodiments, the solvent comprises atleast about 0.001% water, at least about 0.01% water, at least about0.1% water, at least about 1% water, at least about 5%, at least about10%, at least about 20% water, at least about 30% water, at least about40% water, at least about 50% water, or greater. In some embodiments,the solvent may comprise between about 0.1% and about 100% water, about1% to about 90%, about 1% to about 70%, about 1% to about 50%, or about10% to about 50%. In some embodiments, the solvent comprises no morethan about 10% water, about 5% water, about 4% water, about 3% water,about 2% water, about 1% water, or about 0.5% water. In someembodiments, the solvent comprises between about 0.01% water and about5% water, or between about 0.01% water and about 2% water, or betweenabout 0.1% water and about 0.2% water.

Other examples of solvents useful in the methods include, but are notlimited to, non-halogenated hydrocarbon solvents (e.g., pentane, hexane,heptane, cyclohexane), halogenated hydrocarbon solvents (e.g.,dichloromethane, chloroform, fluorobenzene, trifluoromethylbenzene),aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), estersolvents (e.g., ethyl acetate), ether solvents (e.g., tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane), and alcohol solvents (e.g.,ethanol, methanol, propanol, isopropanol, tert-butanol). Othernon-limiting examples of solvents include acetone, acetic acid, formicacid, dimethyl sulfoxide, dimethyl formamide, acetonitrile, p-cresol,glycol, petroleum ether, carbon tetrachloride, hexamethyl-phosphorictriamide, triethylamine, picoline, and pyridine. In some embodiments, aprovided reaction is carried out in a polar solvent, such asacetonitrile. In some embodiments, a solvent may be selected so as toreduce and/or minimize the formation of side products. In certainembodiments, a fluorination reaction is carried out in MeCN as solvent.In certain embodiments, a fluorination reaction is carried out in t-BuOHas solvent. In certain embodiments, a fluorination reaction is carriedout in a mixture of MeCN and t-BuOH as solvent. In certain embodiments,a fluorination reaction is carried out in DMF as solvent. In certainembodiments, a fluorination reaction is carried out in DMSO as solvent.In certain embodiments, a fluorination reaction is carried out in THF assolvent.

In certain embodiments, an anhydrous ¹⁸F-containing solid, optionallycomprising a reagent, may be contacted with a solution of an imagingagent precursor (e.g., a tosylate precursor), and the resulting solutionis heated to an elevated temperature for a select period of time. Asolution may be, for example, an acetonitrile solution. In otherembodiments, a solution of an ¹⁸F species and reagent, if present, iscontacted with a solid imaging agent precursor or a solution of animaging agent precursor.

Some embodiments involve contacting an imaging agent precursor with afluoride species in a solution having a pH below about 13, below about12, or below about 11. In some cases, a solution has a pH between about8 and about 9, or between about 8 and about 10, or between about 7 andabout 8. In certain embodiments, a pH range for the fluorinationreaction is greater than about 6, or greater than about 7, or betweenand including 7-13, between and including 6-12, between and including7-12, between and including 8-12, between and including 9-12, andbetween and including 10-12.

In some cases, a solution comprising a ¹⁸F species, imaging agentprecursor, and, optionally, a reagent, is heated to an elevatedtemperature for a period of time. For example, a solution may be heatedto about 50° C., about 60° C., about 70° C., about 80° C., about 90° C.,about 100° C., about 110° C., about 120° C., about 150° C., about 170°C., about 200° C., about 225° C., about 250° C., or greater, for aperiod of about 5 minutes or less, about 10 minutes or less, about 20minutes or less, about 30 minutes or less. It should be understood thatother temperatures and reaction times may be used. In some embodiments,upon completion of the reaction, the reaction mixture is cooled (e.g.,to room temperature) and optionally diluted with a solvent, such aswater, or mixtures of solvents, such as water/acetonitrile. In someembodiments, a reaction mixture is heated to elevated temperatures toencourage evaporation of the solvent (e.g., to about 95° C.). In someembodiments, a solution is heated to a temperature ranging from about55-125° C. In some cases, a solution is heated to about 65° C., about75° C., about 85° C., about 95° C., about 105° C., about 115° C., orgreater. In some cases, a solution is placed under a reduced pressure ofabout 100 mm Hg, about 125 mm Hg, about 150 mm Hg, about 175 mm Hg,about 200 mm Hg, about 225 mm Hg, about 250 mm Hg, about 275 mm Hg,about 300 mm Hg, about 325 mm Hg, about 350 mm Hg, about 375 mm Hg,about 400 mm Hg, or greater. In some cases, a solution is placed under areduced pressure of about 100 mbar, about 125 mbar, about 150 mbar,about 175 mbar, about 200 mbar, about 225 mbar, about 250 mbar, about275 mbar, about 280 mbar, about 300 mbar, about 325 mbar, about 350mbar, about 375 mbar, about 400 mbar, about 450 mbar, about 500 mbar, orgreater. Those of ordinary skill in the art would be able to selectand/or determine conditions suitable for a particular process. In someembodiments, a solution is concentrated to dryness under a flow of inertgas at about 95° C.

In some embodiments, upon completion of a fluorination reaction, theresulting imaging agent is optionally subjected to one or morepurification steps. In some embodiments, an imaging agent may bereconstituted in a solvent prior to purification (e.g., bychromatography such as HPLC). In some cases, an imaging agent isdissolved in water, acetonitrile, or combinations thereof. In someembodiments, following formation of a solution comprising an imagingagent and a solvent and prior to purification (e.g., by HPLC), thesolution is heated. In a particular embodiment, an imaging agent isreconstituted in a water/acetonitrile mixture and heated (e.g., to atemperature of about 90-100° C.) for about 1 minute, about 3 minutes,about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes,or more. Following heating of the mixture, the solution may beoptionally cooled prior to purification.

C. Purification and Formulation

In some cases, the synthesis, purification, and/or formulation of animaging agent is performed using an automated reaction system optionallycomprising a cassette, wherein the cassette comprises a synthesismodule, a purification module, and/or a formulation module. Automatedreaction systems and cassettes are described herein.

Purification and isolation may be performed using methods known to thoseskilled in the art, including separation techniques like chromatography,or combinations of various separation techniques known in the art, forexample, extractions, distillation, and crystallization. In oneembodiment, high performance liquid chromatography (HPLC) is used with asolvent, or mixture of solvents, as the eluent, to recover the product.In some cases, the eluent includes a mixture of water and acetonitrile,such as a 20:80 water:acetonitrile mixture. The content of water in theeluent may vary from, for example, about 1% to about 30%. In some cases,HPLC purification may be performed using a C-18 column. The product maybe analyzed (e.g., by HPLC) to determine yield (e.g., radiochemicalyield) and/or radiochemical purity. The radiochemical purity may begreater than about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, about 97%, about 98%, about 99%, or more. The percent yieldof a product may be greater than 10%, greater than 20%, greater than30%, greater than 40%, greater than 50%, greater than about 60%, greaterthan about 70%, greater than about 75%, greater than about 80%, greaterthan about 85%, greater than about 90%, greater than about 92%, greaterthan about 95%, greater than about 96%, greater than about 97%, greaterthan about 98%, greater than about 99%, or greater. In some embodiments,the radiochemical yield ranges from 15-50%.

The product may be further processed using additional purificationtechniques, such as filtration. In some cases, the imaging agent ispurified using HPLC, to produce a solution of HPLC mobile phase and theimaging agent. The HPLC mobile phase may be subsequently exchanged for asolution of ascorbic acid or a salt thereof, and ethanol solution, byfiltration through a C-18 resin (e.g., C18 Sep-Pak® cartridge). In someembodiments, the solution of the HPLC mobile phase and the imaging agentis filtered through a C-18 resin, where the imaging agent remains on theresin and the other components, such as acetonitrile and/or othersolvents or components, are removed via elution. The C-18 resin may befurther washed with a solution of ascorbic acid or a salt thereof, andthe filtrate discarded. To recover the purified imaging agent, the C-18resin is washed with a solvent, such as ethanol, and the resultingsolution is optionally further diluted with an ascorbic acid solution ora salt thereof, as described herein.

Optionally, the recovered product is combined with one or morestabilizing agents, such as ascorbic acid or a salt thereof. Forexample, a solution comprising the purified imaging agent may be furtherdiluted with a solution of ascorbic acid or a salt thereof. As describedherein, a formulation may be prepared via an automated reaction systemcomprising a cassette.

In some cases, a solution comprising the imaging agent product may besterile filtered (e.g., using a 13 mm diameter, Millipore, Millex PVDF0.22 μm sterilizing filter) into a sterile product vial. The sterileproduct vial may be a commercially available, pre-sterilized unit thatis not opened during the production process, as any imaging agents (orother components) may be aseptically inserted through the septum priorto use. Those of ordinary skill in the art would be able to selectsuitable vials and production components, including commerciallyavailable, pre-sterilized units comprising a 0.22 μm pore size membraneventing filter and quality control sampling syringes.

Following aseptic filtration, individual doses may be filled insyringes, labeled, and shipped to a clinical site. Dosing administrationtechniques, kits, cassettes, methods and systems (e.g., automatedreaction systems) for synthesis of the imaging agent, and testingprocedures are described herein. In some embodiments, the product isdispensed into a 3 or 5 mL syringe and labeled for distribution. Labelsmay be prepared at a radiopharmacy and applied to a syringe shield andshipping container. Additional labels may be provided in the shippingcontainer for inclusion in clinical site records.

Uses of Imaging Agents

In another aspect, methods of imaging using the imaging agents describedherein are provided. Such methods of imaging a subject includeadministering a composition or formulation that includes an imagingagent as described herein to the subject by injection, infusion, or anyother known method of administration, and imaging a region of interestof the subject. Regions of interest may include, but are not limited to,the heart, a portion of the heart, the cardiovascular system, cardiacvessels, blood vessels (e.g., arteries and/or veins), brain, pancreas,adrenal glands, other organs, and tumors.

In some embodiments, the methods of imaging comprise (a) administeringto a subject a composition that includes a compound as described hereincomprising at least one imaging moiety (e.g., an imaging agent), and (b)acquiring at least one image of at least a portion of the subject. Insome cases, the step of acquiring employs positron emission tomography(PET) for visualizing the distribution of the imaging agent within atleast a portion of the subject. As will be understood by those ofordinary skill in the art, imaging using methods of this disclosure mayinclude full body imaging of a subject, or imaging of a specific bodyregion, organ, or tissue of the subject that is of interest. Forexample, if a subject is known to have, or is suspected of havingmyocardial ischemia, methods of this disclosure may be used to image theheart of the subject. In some embodiments, imaging may be limited to theheart or may include the heart and its associated vasculature.

In some embodiments of the invention, methods of diagnosing or assistingin diagnosing a disease or condition, assessing efficacy of treatment ofa disease or condition, or imaging in a subject with a known orsuspected cardiovascular disease or condition are provided. Acardiovascular disease can be any disease of the heart or other organ ortissue nourished by the vascular system. The vascular system includescoronary arteries, and all peripheral arteries supplying nourishment tothe peripheral vascular system and the brain, as well as veins,arterioles, venules, and capillaries. Examples of cardiovasculardiseases include diseases of the heart, such as coronary artery disease,myocardial infarction, myocardial ischemia, angina pectoris, congestiveheart failure, cardiomyopathy (congenital or acquired), arrhythmia, orvalvular heart disease. In some embodiments, the methods disclosedherein are useful for monitoring and measuring coronary artery diseaseand/or myocardial perfusion. For example, a method described herein candetermine the presence or absence of coronary artery disease and/or thepresence or absence of myocardial infarct. Conditions of the heart mayinclude damage, not brought on by disease but resulting frominjury—e.g., traumatic injury, surgical injury. In some cases, methodsof the invention may include determining a parameter of, or the presenceor absence of, myocardial ischemia, rest (R) and/or stress (S)myocardial blood flows (MBFs), coronary flow reserve (CFR), coronaryartery disease (CAD), left ventricular ejection fraction (LVEF),end-systolic volume (ESV), end-diastolic volume (EDV), and the like.

Without wishing to be bound by any particular theory, an imaging agentas described herein is thought to bind to the mitochondrial complex I ofthe electron transport chain with high affinity. In some embodiments,the imaging agent shows selective uptake to the heart due to the highdensity of mitochondria in the myocardium. Regions of interest mayinclude, but are not limited to, the heart, cardiovascular system,cardiac vessels, blood vessels (e.g., arteries, veins) brain, and otherorgans. A parameter of interest, such as blood flow, cardiac wallmotion, etc., can be imaged and detected using methods and/or systems ofthe invention. In some aspects of the invention, methods for evaluatingperfusion, including myocardial perfusion, are provided.

In some embodiments, a method of imaging a portion of a subjectcomprises administering to the subject a compound (e.g., an imagingagent) as described herein and acquiring at least one image of a portionof the subject. In some embodiments, a method of imaging a portion of asubject comprises administering to a subject a compound as describedherein (e.g., an imaging agent); detecting radiation emitted by thecompound; and forming an image therefrom. In some embodiments, aneffective amount of the compound is administered to the subject.

In some cases, a subject to whom a method of the invention is applied,may have signs or symptoms suggestive of myocardial ischemia ormyocardial infarction. In some cases methods of the invention can beused to identify early or pre-disease conditions that indicate that asubject is at increased risk of a disease. In some instances, methods ofthe invention can be used to determine a subject's risk of futurecardiac events such as myocardial infarction or cardiac death. Imagingmethods of the invention can be used to detect myocardial ischemia insubjects already diagnosed as having a myocardial ischemia disorder orcondition, or in subjects that have no history or diagnosis of such acondition. In other instances, methods of the invention can be used toobtain measurements that provide a diagnosis or aid in providing adiagnosis of a myocardial ischemia disorder or condition. In someinstances, a subject may already be undergoing drug therapy for adisorder or condition associated with myocardial ischemia, while inother instances a subject may not be undergoing therapy for myocardialischemia. In some embodiments, methods of the invention can be used toassess efficacy of a treatment for a disease or condition. For example,the heart can be visualized using imaging agents of the inventionbefore, during, and/or after treatment of a condition affecting theheart of a subject. Such visualization may be used to assess a diseaseor condition and aid in the selection of a treatment regimen, e.g.,therapy, surgery, or medications, for the subject.

A PET imaging agent may have a high first-pass extraction fraction andcan track regional myocardial blood flow over a wide range. Thesefeatures may permit detection of milder decreases in coronary flowreserve and accurate estimation of absolute myocardial blood flow (MBF).PET imaging agents of the invention provide these and other features andare also available as a unit dose from regional PET radiopharmacies,obviating the need for on-site cyclotrons or costly Rb-82 generators.

In some embodiments of the invention, a compound as described herein(e.g., comprising at least one imaging moiety) is used as an imagingagent in combination with positron emission tomography (PET) or withother imaging methods including, but not limited to SPECT imaging. Insome embodiments of the invention, a compound as described hereincomprising at least one imaging moiety is administered to a subject andimaged in the subject using PET. As will be known to those of ordinaryskill in the art, PET is a noninvasive technique that allows serialimages and measurements to be obtained in a single subject over a timeperiod. PET imaging used in methods of the invention may be carried outusing known systems, methods, and/or devices. In some embodiments of theinvention, PET imaging is conducted using a cardiac imaging system. Acardiac imaging system may include PET imaging functionality and acontrol unit configured to drive the imaging functionality to perform aPET imaging procedure on a portion of the subject before, during, and/orafter administration of the imaging agent to the subject. In some cases,the control unit is configured to drive the imaging functionality toperform a PET imaging procedure. The control unit may comprise acomputer system and/or software. In such a case, the computer system maybe programmed or configured to execute the required methods foracquiring and/or analyzing the images. Further, the system may include adata storage device that is readable by a machine, embodying a set ofinstructions executable by the machine to perform the required methodsof acquiring and/or analyzing the images.

The useful dosage of the imaging agent to be administered and theparticular mode of administration will vary depending upon such factorsas age, weight, and particular region to be imaged, as well as theparticular imaging agent used, the diagnostic use contemplated, and theform of the formulation, for example, suspension, emulsion, microsphere,liposome, or the like, as described herein, and as will be readilyapparent to those skilled in the art.

In some embodiments, an imaging agent is administered at a low dosageand the dosage increased until the desirable diagnostic effect isachieved. In one embodiment, the above-described imaging agents may beadministered by intravenous injection, usually in a saline solution, ata dose of about 0.1 to about 100 mCi (and all combinations andsubcombinations of dosage ranges and specific dosages therein), orbetween about 0.5 and about 50 mCi, or between about 0.1 mCi and about30 mCi, or between 0.5 mCi and about 20 mCi. In some embodiments, thedosage range is per 70 kg body weight. For use as nuclear medicineimaging agents, the imaging agent dosages, administered by intravenousinjection, may range from about 0.1 pmol/kg to about 1000 pmol/kg (andall combinations and subcombinations of dosage ranges and specificdosages therein), and in some embodiments, less than 150 pmol/kg.

Imaging systems and components thereof will be known to those ofordinary skill in the art. Many imaging systems and components (e.g.,cameras, software for analyzing the images, etc.) are known andcommercially available, for example, a Siemens Biograph-64 scanner. Anytechnique, software, or equipment that reduces or eliminates motion instatic perfusion images may be used in methods of the invention, becausespatial blurring and artifacts can be caused by patient motion duringimage acquisition. In some embodiments of the invention, images may beacquired in list mode, and may be static, dynamic, or gated images. Anappropriate period of time for acquiring images can be determined by oneof ordinary skill in the art, and may vary depending on the cardiacimaging system, the imaging agent (e.g., amount administered,composition of the imaging agent, subject parameters, area of interest).As used herein a “period of acquiring images” or an “image acquisitionperiod” may be a period of obtaining a single continuous image, or maybe a period during which one or more individual discrete images areobtained. Thus, a period of image acquisition can be a period duringwhich one or more images of one or more regions of a subject areacquired.

In some embodiments of the invention, a period of image acquisitionafter administration of an imaging agent of the invention to a subjectmay be between about 30 seconds and about 60 minutes, between about 1minute and about 30 minutes, between about 5 minutes and about 20minutes, or at least about 1 minute, about 3 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes,about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes,4 about 5 minutes, about 60 minutes, or greater. For example, in arest/stress imaging protocol there would be at least two periods ofimage acquisition with at least one corresponding to the rest segmentand at least one corresponding to the stress segment. In someembodiments, imaging may be continuous over the imaging period of time,or images may be acquired at intervals such as in periodic or gatedimaging.

In some aspects of the invention, gated acquisition is used to acquireimages from a subject to whom an imaging agent has been administered.Gated imaging can be used in various aspects of the invention, and forexample, may provide images of a beating heart of a subject and may beused to attain a functional evaluation of how well a heart is beating.Gated imaging can be performed by acquiring separate images from thesubject at specific intervals during a period of image acquisition. Anon-limiting example of gated imaging is a case when a period of imageacquisition is about 10 minutes long, and images are acquired atrepeated intervals during the 10 minute period. The frequency ofacquisition of images during the period can be set by the operator, forexample, the frequency can be at least every about 1 msec, about 5 msec,about 10 msec, about 20 msec, about 50 msec, about 100 msec, about 125msec, about 250 msec, or more. The length of the interval is set by theoperator to be triggered by an event, such as a cardiac R wave, with thelength of the interval is defined by the number of time bins desired perR wave to R wave interval. Those of skill in the art will be familiarwith the concept and methods of gated image acquisition and can useknown methods to obtain gated images using an imaging agent.

Image acquisition in gated imaging can be triggered at specificintervals, for example, image acquisition can be triggered using an EKGof the heart. In a non-limiting example, an R wave-gated scanner maytrigger acquisition of an image and the mean length of time between oneR wave of a heart and the next can be stored. The number of images tocollect can then be determined. For example, a first image can beacquired at 125 msec, a second image can be acquired at 250 msec, athird image can be acquired at 375 msec, etc. thus images in that Rinterval may be acquired at 125 msec intervals. When the next R intervalbegins, the collection of images resets and image data is then acquiredinto the “first” image at 125 msec from that R interval start time, andthen into the “second” image collected 250 msec from that R intervalstart time, etc. Thus, within each R interval image acquisition is addedinto the initial image of the series and incremented into successiveimages in the series so that a sequence of images can be collected at adesired frequency with the zero time being reset at the start of each Rinterval. Acquired gated images can be used to provide an image of heartmotion and can provide information on heart wall thickness, whether ornot one or more sections of the heart are not moving or beating (e.g., awall motion defect). Use of gated imaging may provide data with which tojudge perfusion of the heart, such as ejection fraction, and tovisualize and identify reduced, absent, paradoxical or asynchronous wallmotion. Use of gated imaging may also provide data with which to improveassessment of myocardial perfusion, judge cardiac function and tovisualize and identify asynchronous wall motion.

In some cases, PET imaging may be used to assess myocardial viabilityvia the ability of this technique to demonstrate metabolic consequencesof myocardial ischemia. Using PET imaging, myocardial segments that arelikely to improve after revascularization can be identified. In somecases, PET imaging may be used in the detection of coronary arterydisease and can also serve as an alternative test for subjects whocannot undergo treadmill exercise stress testing. In some embodiments, astress test method (e.g., pharmacological stress, exercise stress) maybe employed with PET using methods of the invention to qualitatively orquantitatively assess one or more parameters of cardiac function duringinfusion of the imaging agent. Agents for, and methods of, inducingstress, for example, using exercise or pharmacological stress are wellknown in the art. Suitable induction of stress can be carried out usingestablished, known agents and methods. Functions usefully measured usingmethods of the invention include, but are not limited to, in variousembodiments, imaging of myocardial perfusion, imaging, or measurement ofventricular function, and measuring coronary blood flow velocity.

In some cases, methods for imaging the heart of a subject may includeadministering a first dose of an imaging agent to the subject while thesubject is at rest, acquiring at least one first image of the heart,followed by subjecting the subject to stress (e.g., exercise stress orpharmacological stress) and administering a second dose of the imagingagent to the subject during the period of stress, and acquiring at leastone other image of the heart.

In some embodiments, the dose of the imaging agent to be used duringexercise-induced stress in a rest/stress protocol is greater than thatnecessary for pharmacologically-induced stress with the ratio ofexercise-induced stress dose to pharmacologically-induced stress dosebeing greater than or equal to about 1.2, about 1.3, about 1.4, about1.5, about 1.6, about 1.7, about 1.8, about 1.9, or greater. Withrespect to pharmacological stress, in some embodiments of the inventionthat involve rest/stress imaging methods, the dose of the imaging agentadministered for imaging during the pharmacological stress is a minimumof two times the dose of the imaging agent administered for imaging atrest. With respect to exercise stress, in some embodiments of theinvention that involve rest/stress imaging methods, the dose of theimaging agent administered for imaging during the exercise-inducedstress is a minimum of three times the dose of the imaging agentadministered for imaging at rest. In some embodiments of the invention,for imaging first at rest followed by imaging with stress, the dose ofthe imaging agent administered at rest will be lower than the dose ofthe imaging agent administered at stress. In some cases, imaging methodsof the invention may be completed in a single day (e.g., less than about24 hours, less than about 12 hours, less than about 6 hours, less thanabout 4 hours, less than about 2 hours, less than about 1 hour), asdescribed herein. In other cases, methods may be completed in longerperiods of time, e.g., over more than about 24 hours, about 36 hours, orabout 48 hours.

For stress testing in methods, a subject may be subjected to stressusing procedures known to those of ordinary skill in the art. In somecases, the subject may be subjected to stress using procedures includingexercise stress and/or pharmacological stress. Pharmacological stressmay be induced by administering to the subject a pharmacological agentsuch as a vasodilator. Examples of useful pharmacological stress agents,include, but are not limited to adenosine, dobutamine, dipyridamole,regadenoson, binodeneson, apadeneson, and other adenosine A2a receptoragonists. Dosing and administration of pharmacological stress inducingagents, such as vasodilators, are well known in the art and can bedetermined for use in conjunction with methods and systems of theinvention. Exercise stress may be induced using a treadmill, exercisebicycle, hand crank, or other equipment suitable to increase a subject'sheart rate through increased exertion.

An imaging agent may be provided in any suitable form, for example, in apharmaceutically acceptable form. In some cases, an imaging agent isincluded in a pharmaceutically acceptable composition. In someembodiments, an imaging agent is provided as a composition comprisingethanol, sodium ascorbate, and water. In some cases, the compositioncomprises less than 20 weight % ethanol, less than 15 weight % ethanol,less than 10 weight % ethanol, less than 8 weight % ethanol, less than 6weight % ethanol, less than 5 weight % ethanol, less than 4 weight %ethanol, less than 3 weight % ethanol, or less ethanol. In some cases,the composition comprises less than 100 mg/mL, less than 75 mg/mL, lessthan 60 mg/mL, less than 50 mg/mL, less than 40 mg/mL, less than 30mg/mL, or less sodium ascorbate in water. In some embodiments, thecomposition comprises about 20 mg/mL, about 30 mg/mL, about 40 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130mg/mL, about 140 mg/mL, about 150 mg/mL, about 160 mg/mL, about 170mg/mL, about 180 mg/mL, about 190 mg/mL, or about 200 mg/mL. In aparticular non-limiting embodiment, an imaging agent is provided as asolution in water comprising less than 4% ethanol and less than about 50mg/mL sodium ascorbate in water.

In some embodiments, the pH of the composition is between about 1.5 andabout 8, or between about 1.5 and about 7, or between about 1.5 and 6,or between about 1.5 and 5, or between 1.5 and 4, or between 2 and 7, orbetween 3 and 7, or between 4 and 7, or between 5 and 7, or between 5and 6, or between 5.5 and 6. In some embodiments, the pH is about 5.8.In some embodiments, the pH of the composition is about 1.5, about 1.6,about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9,about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, or about 3.5. Insome embodiments, the pH of the composition is between about 1.5 andabout 1.6. In some embodiments, the pH of the composition is betweenabout 1.5 and about 1.9. In some embodiments, the pH of the compositionis between about 2.1 and about 3.5. In some embodiments, the pH of thecomposition is between about 2.4 and about 3.5. In some embodiments, thepH of the composition is between about 2.5 and about 3.5. In someembodiments, the pH of the composition is between 2.1 and about 2.3.

An imaging agent may be provided as composition for injection, which maybe prepared in an injection syringe. For example, the imaging agent maybe prepared by a radiopharmacy (e.g., using the methods describedherein) and/or a PET manufacturing center and provided to a health-careprofessional for administration. In some aspects of the invention, theimaging agent is provided, for example, in a syringe or other container,with ≤50 mg/mL sodium ascorbate in water, ≤4 weight % ethanol, and about1 to 14 mCi of the imaging agent.

In some embodiments, a dose of an imaging agent may be diluted withsaline (e.g., as described herein), if needed to obtain a practical dosevolume. For example, if the activity concentration of an imaging agentis so high that only 0.1 mL is need for an appropriate dose for asubject, the solution can be diluted, e.g., with sterile saline, so thesyringe contains 0.5 ml to 4 or more mL of an imaging agent solution foradministration. In some embodiments of the invention, an injectionvolume for an imaging agent is between 0.5 and 5 mL, 1 and 4 mL, 2 and 3mL, at least 0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9mL, 10 mL, or more. Those of skill in the art will recognize how todilute an imaging agent to produce a sufficient dose volume foradministration. In some embodiments, an imaging agent is provided in acontainer such as a vial, bottle, or syringe, and may be transferred, asnecessary, into a suitable container, such as a syringe foradministration.

Syringes that include an adsorbent plunger tip may result in 10 to 25%of an imaging agent activity remaining in the syringe after injection.Syringes lacking an adsorbent plunger tip may be used, such as a 3 or 5mL NORM-JECT (Henke Sass Wolf, Dudley, Mass.) or other equivalentsyringe lacking an adsorbent plunger tip. Reduction of adsorption in thesyringe can increase the amount of an imaging agent that is transferredfrom the syringe and administered to the subject in methods of theinvention. A syringe used in methods of the invention may comprise animaging agent, and be a non-adsorbing, or reduced adsorbent syringe. Insome embodiments a non-adsorbent or reduced-adsorbent syringe is asyringe that has been coated or treated to reduce adsorption of theimaging agent. In some embodiments, a non-adsorbent or reduced-adsorbentsyringe is a syringe that lacks an adsorbent plunger tip. In someembodiments, a syringe used in conjunction with the invention adsorbsless than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the imaging agent it contains. Incertain aspects of the invention, a syringe that contains an imagingagent does not include a rubber or latex tip on the plunger. In somecases a syringe used in methods of the invention, includes a plungerthat adsorbs less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%,10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of an imaging agentthat the syringe contains. A syringe of the invention may also comprisesodium ascorbate, ethanol, and water, and certain embodiments of theinvention include a syringe containing an imaging agent in a solutioncomprising less than 4 weight % ethanol and less than about 50 mg/mLsodium ascorbate in water. A syringe of the invention may be a syringethat is latex free, rubber free, and/or lubricant free. A syringe of theinvention may contain an imaging agent in an amount between about 1.5and about 14 mCi. A syringe of the invention may contain about 20 mCi orless of an imaging agent.

Components of a composition comprising an imaging agent may be selecteddepending on the mode of administration to the subject. Various modes ofadministration that effectively deliver imaging agents of the inventionto a desired tissue, cell, organ, or bodily fluid will be known to oneof ordinary skill in the art. In some embodiments, the imaging agent isadministered intravenously (e.g., intravenous bolus injection) usingmethods known to those of ordinary skill in the art. As used herein, adose that is “administered to a subject” means an amount of the imagingagent that enters the body of the subject. In some embodiments, due tofactors such as partial retention of an imaging agent in a syringe,tubing, needles, catheter, or other equipment used to administer theimaging agent to a subject, the amount of an imaging agent that ismeasured or determined to be in the a syringe or other equipmentprepared for administration may be more than the amount in the dose thatis administered to the subject. In some embodiments, an injection of animaging agent is followed by a flushing injection of normal saline, intothe subject, using the same tubing, needle, port, etc., used foradministration of an imaging agent. Flushing may be performedimmediately following administration of an imaging agent, or up to 1min, 2 min, 3 min, 5 min, or more, after the administration. The volumeof saline or other agent for flushing may be up to 5 mL, 6 mL, 7 mL, 8mL, 9 mL, 10 mL, 15 mL, 20 mL, or more. As will be understood by thoseof ordinary skill in the art, in embodiments where an imaging agent isadministered using a syringe or other container, the true amount of theimaging agent administered to the subject may be corrected for anyimaging agent that remains in the container. For example, the amount ofradioactivity remaining in the container, and tubing and needle ordelivery instrument that carried the imaging agent from the containerand into the subject can be determined after the imaging agent has beenadministered to the subject and the difference between the startingamount of radioactivity and the amount remaining after administrationindicates the amount that was delivered into the subject. In some cases,the container or injection device (e.g., catheter, syringe) may berinsed with a solution (e.g., saline solution) following administrationof the imaging agent.

In some embodiments of the invention, the total amount of an imagingagent administered to a subject over a given period of time, e.g., inone session, is less than or equal to about 50 mCi, less than or equalto 40 mCi, less than or equal to 30 mCi, less than or equal to 20 mCi,less than or equal to 18 mCi, less than or equal to 16 mCi, less than orequal to 15 mCi, less than or equal to 14 mCi, less than or equal to 13mCi, less than or equal to 12 mCi, less than or equal to 10 mCi, lessthan or equal to 8 mCi, less than or equal to 6 mCi, less than or equalto 4 mCi, less than or equal to 2 mCi, less than or equal to 1 mCi, lessthan or equal to 0.5 mCi. The total amount administered may bedetermined based on a single dose or multiple doses administered to asubject within a given time period of up to 1 minute, 10 minutes, 30minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, ormore.

Based on radiation dose studies, the desirable maximum dose administeredto a subject may be based on determining the amount of an imaging agentwhich limits the radiation dose to about 5 rem to the critical organand/or about 1 rem effective dose (ED) or lower, as will be understoodby those of ordinary skill in the art. In some embodiments, thedesirable maximum dose or total amount of an imaging agent administeredis less than or equal to about 25 mCi, or less than or equal to about 14mCi over a period of time of up to 30 min, 1 hour, 2 hours, 6 hours, 12hours, 24 hours, 48 hours, or more. In some embodiments, the maximumdose of an imaging agent administered to a subject may be less than 3.5μg per 50 kg of body weight per day. That is, in some embodiments of theinvention, the maximum dose of an imaging agent administered to asubject may be less than about 0.07 μg of an imaging agent per kg ofbody weight per day.

Exemplary Cassettes and Reaction Systems

In some embodiments, systems, methods, kits, and cassettes are providedfor the synthesis of an imaging agent as described herein. In someembodiments, an imaging agent may be prepared using an automatedreaction system comprising a disposable or single use cassette. Thecassette may comprise all the non-radioactive reagents, solvents,tubing, valves, reaction vessels, and other apparatus and/or componentsnecessary to carry out the preparation of a given batch of imagingagent. The cassette allows the reaction system to have the flexibilityto make a variety of different imaging agents with minimal risk ofcross-contamination, by simply changing the cassette. By the term“cassette” is meant a piece of apparatus designed to fit removably andinterchangeably onto automated reaction systems, in such a way thatmechanical movement of moving parts of the automated reaction systemcontrols the operation of the cassette from outside the cassette, i.e.,externally. In certain embodiments, a cassette comprises a lineararrangement of valves, each linked to a port where various reagents,cartridges, syringes, and/or vials can be attached, by either needlepuncture of a septum-sealed vial, or by gas-tight, marrying joints. Eachvalve may have a male-female joint which interfaces with a correspondingmoving arm of the automated synthesizer. External rotation of the armcan control the opening or closing of the valve when the cassette isattached to the automated reaction system. Additional moving parts ofthe automated reaction system are designed to clip onto syringe plungertips, and thus raise or depress syringe barrels. An automated reactionsystem may further include a controller and one or more controllablevalves in electrical communication with the controller. An automatedreaction system may also include additional vessels, valves, sensors,heaters, pressurizing elements, etc., in electrical communication withthe controller. An automated reaction system may be operated by acontroller using suitable software for control of valve openings andclosings, heating, cooling, pressure levels, fluid movement, flow rate,etc. The automated reaction system may optionally include a computeroperating system, software, controls, etc., or other component. Inaddition, the automated reaction system may comprise a mount for thecassette. In some embodiments, a cassette of the present inventioncomprises one or more syringes for introducing one or more reagents. Inaddition, in some embodiments, improved methods employed in combinationwith cassettes and automated reactions systems are provided. Use of thecassettes and/or improved methods can result in improved liquid handlingefficiency, resulting in increased imaging agent recovery (e.g., viareduced retention of the imaging agent in the cassette), as describedherein.

Examples of automated reaction systems (e.g., a nucleophilic reactionsystem), include, but are not limited to, the Explora GN or RN synthesissystem (Siemens Medical Solutions USA, Inc.), Tracerlab-MX synthesissystem (GE Healthcare), Eckert & Zeigler Modular-Lab Synthesis system,NEPTIS® synthesis system, etc., which are commonly available at PETmanufacturing facilities.

The automated reaction systems may carry out numerous steps, as outlinedin FIG. 16 , including, but not limited to, preparation of the ¹⁸Ffluoride species, providing an imaging agent precursor, optionally in asolution (e.g., an imaging agent precursor in acetonitrile), aradiolabeling reaction (e.g., reaction of the ¹⁸F species and theimaging agent precursor to form the imaging agent) optionally in asynthesis module, purification (e.g., by preparative HPLC), solventexchange (e.g., by Sep-Pak), aseptic filtration, and release into acontainer. For example, see Example 68.

In some embodiments, the automated reaction system may make use of acassette comprising a reaction module in fluid connection with apurification module and/or a formulation module. FIG. 17 shows aschematic representation of a cassette in connection with exemplaryreaction systems for synthesizing an imaging agent comprising a reactionmodule, a purification module, and/or a formulation module, according tosome embodiments.

In some embodiments, the reaction module may include a reaction chamberin which conversion of the imaging agent precursor to the imaging agentis performed. The reaction module may include a source of a fluoridespecies (e.g., ¹⁸F), a source of the imaging agent precursor, a sourceof an additive (e.g., salt additive), and other sources of additionalcomponents such as solvents, each of which may optionally be fluidlyconnected to the reaction chamber. In some embodiments, one or morereagents are provided via a syringe as opposed to vials or reservoirs aspreviously reported. The reaction module may also comprise an anionexchange column for purification of the fluoride species, prior tointroduction into the reaction chamber.

Upon reaction, the resulting imaging agent product is transferred fromthe reaction module to the purification module for further processing,treatment, and/or purification. The purification module may include, forexample, a column (e.g., an HPLC column) fluidly connected to one ormore sources of solvents to be used as eluents. The purification modulemay further comprise a source of a stabilizing agent (e.g., ascorbicacid or a salt thereof), which may be added to the imaging agent uponpurification (e.g., by HPLC). The purified imaging agent is thentransferred to the formulation module, where further purification andformulation may be performed. The formulation module may include afilter for aseptic filtration and/or a C-18 column for solvent exchange.

In some embodiments, a cassette comprises a reaction module and aformulation module. A reaction module of the invention may include asource of ¹⁸F, a filter to remove unreacted [¹⁸O]H₂O, a source of anammonium salt, a source for a diluent for the ¹⁸F, a source for animaging agent precursor, a source for an H₂O diluent for the imagingagent precursor, a reaction vessel for reacting the ¹⁸F and the imagingagent precursor, a solid phase extraction column (e.g., a C-18 column,or other suitable column) in fluid communication with the reactionvessel. The solid phase extraction column includes a solid sorbent toadsorb the radiolabeled imaging agent product on the sorbent. At least aportion of the residual reaction impurities pass through solid phaseextraction column without adsorbing on the sorbent. The reaction modulealso includes a source of wash solutions in fluid communication with thesolid phase extraction column for providing wash solutions to elute theremaining impurities on the sorbent, and includes a source of an eluent(e.g., as H₂O/MeCN, or other suitable eluent) in fluid communicationwith the solid phase extraction column for eluting the radiolabeledimaging agent product off the sorbent. The reaction module may alsoinclude a source of a diluent for the eluted radiolabeled imaging agent.

A formulation module of an apparatus of the invention may be in fluidcommunication with a reaction module and may include a solid phaseextraction cartridge that includes a solid sorbent (e.g., C-18, or othersuitable sorbent) to adsorb the diluted radiolabeled imaging agent, asource of wash solutions (e.g., comprising ascorbic acid, a saltthereof, or other suitable wash solution) in fluid communication withthe solid phase extraction cartridge for providing wash solutions towash off any remaining impurities on the sorbent, and a source ofeluting fluid (e.g., ethanol, or other suitable eluting fluid) in fluidcommunication with the solid phase extraction cartridge for eluting theradiolabeled imaging agent product off the sorbent. In some embodiments,the wash solution(s) is provided in a syringe which may provide certainadvantages, as described herein. The formulation module may also includea source of a diluent (e.g., comprising ascorbic acid, a salt thereof,or other suitable diluent), for diluting the eluted radiolabeled imagingagent. The formulation module may also be in fluid communication with asterilizing filter (e.g., a Sartorius Minisart RC15 sterilizing filter,or other suitable sterilizing filter).

In a particular embodiment, a cassette is provided for use with anautomated synthesis module, for example, a GE TracerLab MX synthesismodule. In one embodiment, a cassette comprises a disposable sterilizedassembly of molded stopcock manifolds specifically designed for use withthe automated synthesis module (e.g., GE TracerLab MX synthesis module).Individual manifolds are connected in a linear or non-linear fashion toform a directional array that dictates the flow path of reagents used inthe preparation of an imaging agent. In some embodiments, the main bodyof the cassette contains at least one manifold comprising a plurality ofmanifold positions (e.g., stockcocks). For example, the main body maycomprise at least one, two, three, four or more, manifolds. The cassettemay comprise between 1 to 20 manifold positions, between 1 to 15manifold positions, between 5 and 20 manifold positions, between 5 and15 manifold positions. Each of the manifolds may or may not besymmetrical. In one embodiment, the main body of the cassette containsthree plastic manifolds each fitted with five standard molded stopcocks,thereby having a total of 15 total manifold positions. Individualstopcocks are adapted with luer fittings to accommodate solvents,reagents, syringes, tubing required for gas and liquid handling, etc.The stopcocks are adapted for solvents and reagents and may be fittedwith plastic spikes upon which inverted punch vials are located, whilethose featuring tubing and syringes are fitted with male luerconnections according to function. In some embodiments, the cassettecomprises a linear arrangement of a plurality of stopcock manifoldsconnected to one or more of the components selected from the groupconsisting of a gas inlet, anion exchange cartridge, C-18 cartridge,syringe, solvent reservoir, reaction vessel, HPLC system, collectionvessel, reservoirs for solutions of ascorbic acid or salt thereof, andexhaust outlet. In some embodiments, the reservoirs for solutions ofascorbic acid or salt thereof comprise a syringe. In some cases, thecassette further comprises tubing. In some cases, the cassette furthercomprises an imaging agent synthesis module, wherein the apparatus isfluidically connected to the cassette. In some cases, the apparatus iscapable carrying out the method of synthesizing an imaging agent asdescribed herein.

In some embodiments, the cassette configuration provided for thepreparation of an imaging agent is depicted in FIG. 17 . In someembodiments, the cassette configuration comprises a linear arrangementof a plurality of stopcock manifolds arranged in the order:

-   -   1) luer connections (2) to gas inlet and [¹⁸O]H₂O recovery;    -   2) anion exchange cartridge column eluting solution (optionally        1 mL punch vial);    -   3) spike connection for acetonitrile (optionally 10 mL punch        vial);    -   4) empty syringe (optionally 30 mL);    -   5) reservoir with solution of imaging agent precursor        (optionally 10 mL punch vial);    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe (optionally 20 mL) with solution of ascorbic acid or        salt thereof (e.g., at pH 2);    -   9) inlet from HPLC;    -   10) ethanol reservoir (optionally 3 mL syringe);    -   11) syringe (optionally 10 mL) with solution of ascorbic acid or        salt thereof (e.g., at pH 5.8);    -   12) syringe (optionally 5 mL) with water;    -   13) final product vial;    -   14) empty syringe (optionally 30 mL); and    -   15) reaction vessel and exhaust.

In some embodiments, the linear arrangement disclosed above can bechanged to switch the reagent at position 3 with the reagent at position5 and/or to switch the reagent at position 11 with the reagent atposition 13.

The cassettes and corresponding methods described herein provideunexpected results as compared to previously described cassettes andmethods. In some cases, the use of syringes as reservoirs for reagents(e.g., ascorbic acid or salt thereof) results in overall reducedproduction cost and improved liquid handling efficiency during themanufacture of an imaging agent. In addition, a variation in theconfiguration of the placement of the components of the cassette alsoresults in improved liquid handling efficiency as well as increased drugproduct recovery during the manufacture of an imaging agent. This may bedue to reduced exposure to the plastic manifold which can result in lessadsorption of the imaging agent during the delivery process. In somecases, the variation of the cassette comprises repositioning one of thereagents (e.g., to position 11) and the final product vial (e.g., toposition 13). In some embodiments, improved methods of use of thecassettes are provided. In some embodiments, computer control of thecassettes is employed to execute a unique sequence of mechanical eventsdictated by the individual tracers. In some cases, a discrete sequencefile is employed to describe the essential synthetic parameters (e.g.reaction time and temperature) and to adapt the preferred reagent andcassette configuration for the selected imaging agent. In someembodiments, sequence modifications as compared to previously describedmethods may be incorporated based upon the novel reagent containers(e.g., syringes) and cassette configurations as described herein. Forexample, in some embodiments, unique programming sequences are employedto add nitrogen gas into the syringe containers thereby providing forcomplete reagent transfer. Additionally, for example, in someembodiments, overall sequence timing is modified as compared topreviously described methods to provide shorter sequence durations(e.g., such that preparatory occurs in a parallel fashion rather than asa linear series).

Exemplary Kits

In some embodiments, systems, methods, kits, and cassettes kits for thepreparation of an imaging agent are provided for detecting, imaging,and/or monitoring myocardial perfusion. In some embodiments, kits forthe administration of an imaging agent are provided. Kits of theinvention may include, for example, a container comprising an imagingagent or an imaging agent precursor, and instructions for use. Kits mayinclude a sterile, non-pyrogenic, formulation comprising a predeterminedamount of an imaging agent or precursor thereof and optionally othercomponents. In some aspects of the invention, a kit may include one ormore syringes that contain an imaging agent or precursor thereof to beprepared for administration to a subject. A container that may be usedin conjunction with an imaging agent (e.g., to deliver and/or administeran imaging agent to a subject) may be a syringe, bottle, vial, tubes,etc. Exemplary syringes that may be included in a kit of the inventionare syringes lacking an adsorbent plunger tip, such as a 3 or 5 mLNORM-JECT (Henke Sass Wolf, Dudley, Mass.), or other equivalent syringelacking an adsorbent plunger tip. An imaging agent or precursor thereofmay be provided in a kit and additional preparations before use mayoptionally include diluting the imaging agent to a usable concentration.Instructions in a kit of the invention may relate to methods forpreparing the imaging agent, methods of diluting the imaging agent,methods of administering the imaging agent to a subject for diagnosticimaging, or other instructions for use.

In some cases, a kit can also include one or more vials containing adiluent for preparing an imaging agent composition for administration toa subject (e.g., human). A diluent vial may contain a diluent such asphysiological saline, water, buffered solution, etc. for diluting animaging agent. For example, the imaging agent may be packaged in a kitin a ready-to-inject formulation, or may require some reconstitution ordilution whereby a final composition/formulation for injection orinfusion is prepared.

Instructions in a kit of the invention may also include instructions foradministering the imaging agent to a subject and may include informationon dosing, timing, stress induction, etc. For example, a kit may includean imaging agent or precursor thereof described herein, along withinstructions describing the intended application and the properadministration of the agent. As used herein, “instructions” can define acomponent of instruction and/or promotion, and typically involve writteninstructions on or associated with packaging of the invention.Instructions also can include any oral or electronic instructionsprovided in any manner such that a user will clearly recognize that theinstructions are to be associated with the kit, for example, audiovisual(e.g., videotape, DVD, etc.), Internet, and/or web-based communications,etc. The written instructions may be in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which instructions can alsoreflect approval by the agency of manufacture, use or sale for humanadministration. In some cases, the instructions can include instructionsfor mixing a particular amount of the diluent with a particular amountof a concentrated solution of the imaging agent or precursor thereof ora solid preparation of the imaging agent, or precursor thereof whereby afinal formulation for injection or infusion is prepared for example,such that the resulting solution is at a suitable concentration foradministration to a subject (e.g., at a concentration as describedherein). A kit may include a whole treatment regimen of the inventivecompound (e.g., a rest dose and a stress dose).

The kit may contain any one or more of the components described hereinin one or more containers. As an example, in one embodiment, the kit mayinclude instructions for mixing one or more components of the kit and/orisolating and mixing a sample and applying to a subject. The kit mayinclude a container housing an agent described herein. The agent may bein the form of a liquid, gel or solid (powder). The agent may beprepared sterilely, packaged in syringe and shipped refrigerated.Alternatively it may be housed in a vial or other container for storage.A second container may have other agents prepared sterilely.Alternatively the kit may include an active agent premixed and shippedin a syringe, vial, tube, or other container. The kit may have one ormore or all of the components required to administer the agents to apatient, such as a syringe, topical application devices, or iv needletubing and bag.

It also will be understood that containers containing the components ofa kit of the invention, whether the container is a bottle, a vial (e.g.,with a septum), an ampoule, an infusion bag, or the like, can includeadditional indicia such as conventional markings that change color whenthe preparation has been autoclaved or otherwise sterilized. A kit ofthe invention may further include other components, such as syringes,labels, vials, tubing, catheters, needles, ports, and the like. In someaspect of the invention, a kit may include one or more syringescontaining the imaging agent sufficient for administration.

Buffers useful in the preparation of imaging agents or precursor thereofand kits include, for example, phosphate, citrate, sulfosalicylate, andacetate buffers. A more complete list can be found in the United StatesPharmacopoeia. Lyophilization aids useful in the preparation of imagingagents and kits include, for example, mannitol, lactose, sorbitol,dextran, FICOLL® polymer, and polyvinylpyrrolidine (PVP). Stabilizationaids useful in the preparation of imaging agents and kits include, forexample, ascorbic acid, cysteine, monothioglycerol, sodium bisulfite,sodium metabisulfite, gentisic acid, and inositol. Solubilization aidsuseful in the preparation of imaging agents and kits include, forexample, ethanol, glycerin, polyethylene glycol, propylene glycol,polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates,poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers(“Pluronics”) and lecithin. In certain embodiments, the solubilizingaids are polyethylene glycol, cyclodextrins, and Pluronics.Bacteriostats useful in the preparation of imaging agents and kitsinclude, for example, benzyl alcohol, benzalkonium chloride,chlorbutanol, and methyl, propyl, or butyl paraben.

Pharmaceutical Compositions

Once a compound as described herein (e.g., an imaging agent) has beenprepared or obtained, it may be combined with one or morepharmaceutically acceptable excipients to form a pharmaceuticalcomposition that is suitable for administration to a subject, includinga human. As would be appreciated by one of skill in this art, theexcipients may be chosen, for example, based on the route ofadministration as described below, the imaging agent being delivered,time course of delivery of the agent, and/or the health/condition of thesubject. The pharmaceutical composition may be a solid or liquid.

Pharmaceutical compositions of the present invention and for use inaccordance with the present invention may include a pharmaceuticallyacceptable excipient or carrier. As used herein, the term“pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose, and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose, andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil; safflower oil; sesame oil; olive oil; corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; detergents such as Tween 80; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations informulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrierand/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping and/or packaging the product into a desiredsingle or multidose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and combinationsthereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium iodide, sodiummetabisulfite, sodium nitrite, sodium sulfite, and sodium thiosulfate.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorohexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an antioxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, Dgluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical Mantoux method of intradermaladministration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

The pharmaceutical compositions of this invention can be administered tohumans and/or to other animals parenterally (e.g., by intravenous,intramuscular, subcutaneous, or intraperitoneal injection). The mode ofadministration will vary depending on the intended use, as is well knownin the art.

FURTHER EMBODIMENTS

Certain embodiments are further contemplated herein.

Embodiment 1

In embodiment 1, provided is a compound comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, heterocyclyl, or aryl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound;and

provided that when W is aryl, a) R³ is not halo, alkyl or haloalkyl, orb) at least one R⁶ is selected from the group consisting of alkynyloptionally substituted, alkenyl optionally substituted, alkylsubstituted with —CN, alkyl substituted with —C(═O)OR⁸, alkylsubstituted with —C(═O)R⁸, alkyl substituted with —N(R⁷)₂, —CN, —NO₂,—N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸, —C(═O)R⁸, —C(═O)N(R⁷)₂, and—N(R⁷)C(═O)R⁸.

Embodiment 2

The compound of embodiment 1, wherein the compound comprises thestructure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, or heterocyclyl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 3

The compound of embodiment 1 or 2, wherein W is heteroaryl.

Embodiment 4

The compound of embodiment 1 or 2, wherein W is naphthyl.

Embodiment 5

The compound of embodiment 1 or 2, wherein W is heterocyclyl.

Embodiment 6

The compound of embodiment 1 or 2, wherein W is:

wherein each X is independently selected from the group consisting of C,C(R⁶), C(R⁶)₂, N, NR⁷, O, and S; and

wherein each

is independently a single or double bond,

provided at least one X is not C or C(R⁶).

Embodiment 7

The compound of embodiment 1 or 2, wherein W is:

wherein each X is independently C, C(R⁶) or N, provided at least one Xis not C or C(R⁶).

Embodiment 8

The compound of embodiment 1 or 2, wherein W is:

Embodiment 9

The compound of embodiment 1 or 2, wherein W is:

wherein R^(6′) is halo or hydrogen; and optionally, wherein R^(6′) isfluoro, chloro, bromo, or hydrogen.

Embodiment 10

The compound of embodiment 9, wherein R⁶ is —O(CH₂)_(j)I_(m); wherein jis 1, 2, 3, 4, 5, or 6; and optionally, wherein I_(m) is ¹⁸F.

Embodiment 11

The compound of embodiment 9, wherein R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6; and optionally, wherein I_(m) is ¹⁸F.

Embodiment 12

The compound of embodiment 1 or 2, wherein W is:

Embodiment 13

The compound of embodiment 1 or 2, wherein W is:

each X is independently selected from the group consisting of C, C(R⁶),C(R⁶)₂, N, NR⁷, O, and S; and

each

is independently a single or double bond,

provided at least one X is not C or C(R⁶).

Embodiment 14

The compound of embodiment 1 or 2, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 15

The compound of embodiment 1 or 2, wherein the compound comprises thestructure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

Q has the structure:

each Y and each X is independently selected from the group consisting ofC, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least one Y is not C orC(R⁶), optionally, wherein one X and/or one Y is absent;

each

is independently a single or double bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 16

The compound of embodiment 15, wherein each Y and each X isindependently selected from the group consisting of C, C(R⁶), C(R⁶)₂, N,NR⁷, O, and S, provided at least one Y is not C or C(R⁶).

Embodiment 17

The compound of embodiment 15, wherein one Y is absent or one X isabsent.

Embodiment 18

The compound of embodiment 15, wherein Q is:

Embodiment 19

The compound of any one of embodiments 1-13 and 15-18, wherein the atleast one imaging moiety is present in R¹, R², R³, R⁴, R⁵, or R⁶.

Embodiment 20

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ isalkyl optionally substituted.

Embodiment 21

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 22

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ is—C(CH₃)₂CH₂OH.

Embodiment 23

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ ist-butyl.

Embodiment 24

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ isaryl optionally substituted.

Embodiment 25

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ isphenyl optionally substituted.

Embodiment 26

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ isunsubstituted phenyl.

Embodiment 27

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ iscycloalkyl optionally substituted.

Embodiment 28

The compound of any one of embodiments 1-13 and 15-19, wherein R¹ iscyclohexyl optionally substituted.

Embodiment 29

The compound of any one of embodiments 1-13 and 15-28, wherein R² is H.

Embodiment 30

The compound of any one of embodiments 1-13 and 15-29, wherein J is abond.

Embodiment 31

The compound of any one of embodiments 1-13 and 15-29, wherein J is O.

Embodiment 32

The compound of any one of embodiments 1-13 and 15-29, wherein J is S.

Embodiment 33

The compound of any one of embodiments 1-13 and 15-32, wherein n is 0.

Embodiment 34

The compound of any one of embodiments 1-13 and 15-32, wherein n is 1.

Embodiment 35

The compound of any one of embodiments 1-13 and 15-32, wherein n is 2.

Embodiment 36

The compound of any one of embodiments 1-13 and 15-32, wherein n is 3.

Embodiment 37

The compound of any one of embodiments 1-13 and 15-36, wherein each ofR⁴ and R⁵ is H.

Embodiment 38

The compound of any one of embodiments 1-13 and 15-36, wherein at leastone R⁴ and R⁵ is ²H, and optionally, wherein each of R⁴ and R⁵ is ²H.

Embodiment 39

The compound of any one of embodiments 1-13 and 15-38, wherein R³ ishalo.

Embodiment 40

The compound of any one of embodiments 1-13 and 15-38, wherein R³ is Cl.

Embodiment 41

The compound of any one of embodiments 1-13 and 15-38, wherein R³ is Br.

Embodiment 42

The compound of any one of embodiments 1-13 and 15-38, wherein R³ is H.

Embodiment 43

The compound of any one of embodiments 1-13 and 15-38, wherein R³ isalkyl optionally substituted.

Embodiment 44

The compound of any one of embodiments 1-13 and 15-38, wherein R³ isunsubstituted alkyl.

Embodiment 45

The compound of any one of embodiments 1-13 and 15-38, wherein R³ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 46

The compound of any one of embodiments 1-13 and 15-38, wherein R³ ismethyl.

Embodiment 47

The compound of embodiment 1, wherein the compound comprises thestructure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, unsubstitutedalkyl or alkyl optionally substituted with a moiety other than ahalogen, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, —CN, and —NO₂;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, or 5;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 48

The compound of embodiment 47, wherein R³ is alkyl optionallysubstituted.

Embodiment 49

The compound of embodiment 47, wherein R³ is unsubstituted alkyl.

Embodiment 50

The compound of embodiment 47, wherein R³ is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 51

The compound of embodiment 47, wherein R³ is methyl.

Embodiment 52

The compound of any one of embodiments 47-51, wherein the at least oneimaging moiety is present in R¹, R², R³, R⁴, R⁵, or R⁶.

Embodiment 53

The compound of any one of embodiments 47-52, wherein R¹ is alkyloptionally substituted.

Embodiment 54

The compound of any one of embodiments 47-52, wherein R¹ is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 55

The compound of any one of embodiments 47-52, wherein R¹ is—C(CH₃)₂CH₂OH.

Embodiment 56

The compound of any one of embodiments 47-52, wherein R¹ is t-butyl.

Embodiment 57

The compound of any one of embodiments 47-52, wherein R¹ is aryloptionally substituted.

Embodiment 58

The compound of any one of embodiments 47-52, wherein R¹ is phenyloptionally substituted.

Embodiment 59

The compound of any one of embodiments 47-52, wherein R¹ isunsubstituted phenyl.

Embodiment 60

The compound of any one of embodiments 47-52, wherein R¹ is cycloalkyloptionally substituted.

Embodiment 61

The compound of any one of embodiments 47-52, wherein R¹ is cyclohexyloptionally substituted.

Embodiment 62

The compound of any one of embodiments 47-61, wherein R² is H.

Embodiment 63

The compound of any one of embodiments 47-62, wherein J is a bond.

Embodiment 64

The compound of any one of embodiments 47-62, wherein J is O.

Embodiment 65

The compound of any one of embodiments 47-62, wherein J is S.

Embodiment 66

The compound of any one of embodiments 47-65, wherein n is 0.

Embodiment 67

The compound of any one of embodiments 47-65, wherein n is 1.

Embodiment 68

The compound of any one of embodiments 47-65, wherein n is 2.

Embodiment 69

The compound of any one of embodiments 47-68, wherein each of R⁴ and R⁵is H.

Embodiment 70

The compound of any one of embodiments 47-68, wherein at least one R⁴and R⁵ is ²H, and optionally, wherein each of R⁴ and R⁵ is ²H.

Embodiment 71

The compound of embodiment 47, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 72

In embodiment 72, provided is a compound comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

each R⁴, R⁵, and R¹¹ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

q, and r are each independently 0, 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 73

In embodiment 73, provided is a compound comprising the structure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, —NO₂, haloalkyl,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷)₂, N(R⁷)C(═O), and —CH₂O;

each R⁴ and R⁵ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

n is 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 74

The compound of embodiment 72 or 73, wherein Z is aryl.

Embodiment 75

The compound of embodiment 72 or 73, wherein Z is phenyl.

Embodiment 76

The compound of embodiment 72 or 73, wherein Z is naphthyl.

Embodiment 77

The compound of embodiment 72 or 73, wherein Z is heteroaryl.

Embodiment 78

The compound of embodiment 72 or 73, wherein Z is heterocyclyl.

Embodiment 79

The compound of embodiment 72 or 73, wherein Z is:

wherein each X is independently selected from the group consisting of C,C(R⁶), C(R⁶)₂, N, NR⁷, O, and S; and

wherein each

is independently a single or double bond.

Embodiment 80

The compound of embodiment 72 or 73, wherein Z is:

-   -   wherein each X is independently C, C(R⁶) or N.

Embodiment 81

The compound of embodiment 79 or 80, wherein at least one X is not C orC(R⁶).

Embodiment 82

The compound of embodiment 72, 73, or 80, wherein Z is:

Embodiment 83

The compound of embodiment 72, 73, or 80, wherein Z is:

wherein R^(6′) is halo or hydrogen.

Embodiment 84

The compound of embodiment 83, wherein R^(6′) is fluoro, chloro, bromo,or hydrogen.

Embodiment 85

The compound of embodiment 83, wherein R⁶ is —O(CH₂)_(j)I_(m); whereinI_(m) is an imaging moiety and j is 1, 2, 3, 4, 5, or 6.

Embodiment 86

The compound of embodiment 83, wherein R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6.

Embodiment 87

The compound of embodiment 72 or 73, wherein Z is:

Embodiment 88

The compound of embodiment 72 or 73, wherein Z is:

each X is independently selected from the group consisting of C, C(R⁶),C(R⁶)₂, N, NR⁷, O, and S; and

each

is independently a single or double bond.

Embodiment 89

The compound of embodiment 88, wherein at least one X is not C or C(R⁶).

Embodiment 90

The compound of embodiment 72 or 73, wherein Z has the structure:

each Y and each X is independently selected from the group consisting ofC, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S;

each

is independently a single or double bond.

Embodiment 91

The compound of embodiment 90, wherein at least one Y is not C or C(R⁶).

Embodiment 92

The compound of embodiment 90 or 91, wherein at least one X is not C orC(R⁶).

Embodiment 93

The compound of embodiment 72, 73, or 90, wherein Z is:

Embodiment 94

The compound of embodiment 72, 73, or 90, wherein Z is:

Embodiment 95

The compound of any one of embodiments 73 or 72-94, wherein J is a bond.

Embodiment 96

The compound of any one of embodiments 73 or 72-94, wherein J is O.

Embodiment 97

The compound of any one of embodiments 73 or 72-94, wherein J is S.

Embodiment 98

The compound of any one of embodiments 72-97, wherein q is 0.

Embodiment 99

The compound of any one of embodiments 72-97, wherein q is 1.

Embodiment 100

The compound of any one of embodiments 72-97, wherein q is 2.

Embodiment 101

The compound of any one of embodiments 72-100, wherein r is 0.

Embodiment 102

The compound of any one of embodiments 72-100, wherein r is 1.

Embodiment 103

The compound of any one of embodiments 72-100, wherein r is 2.

Embodiment 104

The compound of any one of embodiments 72-97, wherein q and r are each0.

Embodiment 105

The compound of any one of embodiments 72-97, wherein q and r are each1.

Embodiment 106

The compound of any one of embodiments 73 or 74-83, wherein n is 0.

Embodiment 107

The compound of any one of embodiments 73 or 74-83, wherein n is 1.

Embodiment 108

The compound of any one of embodiments 73 or 74-83, wherein n is 2.

Embodiment 109

The compound of any one of embodiments 72-91, or 107-108, wherein eachof R⁴ and R⁵ is H.

Embodiment 110

The compound of any one of embodiments 72-109, wherein each R¹¹ is H.

Embodiment 111

The compound of any one of embodiments 73 or 72-110, wherein the atleast one imaging moiety is present in R¹, R², R³, R⁴, R⁵, R⁶, or R¹¹.

Embodiment 112

The compound of any one of embodiments 73 or 72-111, wherein R¹ is alkyloptionally substituted.

Embodiment 113

The compound of any one of embodiments 73 or 72-111, wherein R¹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 114

The compound of any one of embodiments 73 or 72-111, wherein R¹ is—C(CH₃)₂CH₂OH.

Embodiment 115

The compound of any one of embodiments 73 or 72-111, wherein R¹ ist-butyl.

Embodiment 116

The compound of any one of embodiments 73 or 72-111, wherein R¹ is aryloptionally substituted.

Embodiment 117

The compound of any one of embodiments 73 or 72-111, wherein R¹ isphenyl optionally substituted.

Embodiment 118

The compound of any one of embodiments 73 or 72-111, wherein R¹ isunsubstituted phenyl.

Embodiment 119

The compound of any one of embodiments 73 or 72-111, wherein R¹ iscycloalkyl optionally substituted.

Embodiment 120

The compound of any one of embodiments 73 or 72-111, wherein R¹ iscyclohexyl optionally substituted.

Embodiment 121

The compound of any one of embodiments 73 or 72-120, wherein R² is H.

Embodiment 122

The compound of any one of embodiments 73 or 72-121, wherein R³ is halo.

Embodiment 123

The compound of any one of embodiments 73 or 72-121, wherein R³ is Cl.

Embodiment 124

The compound of any one of embodiments 73 or 72-121, wherein R³ is Br.

Embodiment 125

The compound of any one of embodiments 73 or 72-121, wherein R³ is H.

Embodiment 126

The compound of any one of embodiments 73 or 72-121, wherein R³ is alkyloptionally substituted.

Embodiment 127

The compound of any one of embodiments 73 or 72-121, wherein R³ isunsubstituted alkyl.

Embodiment 128

The compound of any one of embodiments 73 or 72-121, wherein R³ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 129

The compound of any one of embodiments 73 or 72-121, wherein R³ ismethyl.

Embodiment 130

The compound of embodiment 72, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 131

The compound of embodiment 73, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 132

The compound of embodiment 1, wherein the compound comprises thestructure:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and an imaging moiety;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and an imaging moiety;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and an imaging moiety;

J is selected from the group consisting of consisting of N(R⁷), S, O,C(═O), C(═O)O, OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and an imaging moiety, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and animaging moiety;

p is 0, 1, 2, 3, or 4;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

R¹² is selected from the group consisting of alkynyl optionallysubstituted, alkenyl optionally substituted, alkyl substituted with —CN,alkyl substituted with —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkylsubstituted with —N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)R⁸, —C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R⁸;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety,

provided that at least one imaging moiety is present in the compound.

Embodiment 133

The compound of embodiment 132, wherein R¹² is —NO₂,—C(═O)(CH₂)_(u)I_(m), —C(═O)O(CH₂)_(u)I_(m), —C≡C(CH₂)_(u)I_(m), or—Si(alkyl)₂I_(m); wherein I_(m) is an imaging moiety and u is 1, 2, 3,4, 5, or 6.

Embodiment 134

The compound of any one of embodiments 132-133, wherein the at least oneimaging moiety is present in R¹, R², R³, R⁴, R⁵, R⁶, or R¹².

Embodiment 135

The compound of any one of embodiments 132-133, wherein the at least oneimaging moiety is present in R¹, R³, R⁴, R⁵, R⁶, or R¹².

Embodiment 136

The compound of any one of embodiments 132-134, wherein R¹ is alkyloptionally substituted.

Embodiment 137

The compound of any one of embodiments 132-134, wherein R¹ is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 138

The compound of any one of embodiments 132-134, wherein R¹ is—C(CH₃)₂CH₂OH.

Embodiment 139

The compound of any one of embodiments 132-134, wherein R¹ is t-butyl.

Embodiment 140

The compound of any one of embodiments 132-134, wherein R¹ is aryloptionally substituted.

Embodiment 141

The compound of any one of embodiments 132-134, wherein R¹ is phenyloptionally substituted.

Embodiment 142

The compound of any one of embodiments 132-134, wherein R¹ isunsubstituted phenyl.

Embodiment 143

The compound of any one of embodiments 132-134, wherein R¹ is cycloalkyloptionally substituted.

Embodiment 144

The compound of any one of embodiments 132-134, wherein R¹ is cyclohexyloptionally substituted.

Embodiment 145

The compound of any one of embodiments 132-144, wherein R² is H.

Embodiment 146

The compound of any one of embodiments 132-145, wherein J is a bond.

Embodiment 147

The compound of any one of embodiments 132-145, wherein J is O.

Embodiment 148

The compound of any one of embodiments 132-145, wherein J is S.

Embodiment 149

The compound of any one of embodiments 132-148, wherein n is 0.

Embodiment 150

The compound of any one of embodiments 132-148, wherein n is 1.

Embodiment 151

The compound of any one of embodiments 132-148, wherein n is 2.

Embodiment 152

The compound of any one of embodiments 132-151, wherein each of R⁴ andR⁵ is H.

Embodiment 153

The compound of any one of embodiments 132-151, wherein at least one R⁴and R⁵ is ²H, and optionally, wherein each of R⁴ and R⁵ is ²H.

Embodiment 154

The compound of any one of embodiments 132-153, wherein R³ is halo.

Embodiment 155

The compound of any one of embodiments 132-153, wherein R³ is Cl.

Embodiment 156

The compound of any one of embodiments 132-153, wherein R³ is Br.

Embodiment 157

The compound of any one of embodiments 132-153, wherein R³ is H.

Embodiment 158

The compound of any one of embodiments 132-153, wherein R³ is alkyloptionally substituted.

Embodiment 159

The compound of any one of embodiments 132-153, wherein R³ isunsubstituted alkyl.

Embodiment 160

The compound of any one of embodiments 132-153, wherein R³ is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 161

The compound of any one of embodiments 132-153, wherein R³ is methyl.

Embodiment 162

The compound of embodiment 132, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 163

The compound of any one of embodiments 1-13, 15-70, 72-124, and 132-161,wherein the at least one imaging moiety is present in R⁶.

Embodiment 164

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163, wherein at least one R⁶ is substituted with the at least oneimaging moiety.

Embodiment 165

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-164, wherein the at least one imaging moiety is selected from thegroup consisting of ¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I,^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga.

Embodiment 166

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-165, wherein the at least one imaging moiety is ¹⁸F.

Embodiment 167

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-165, wherein the at least one imaging moiety is associated with agroup comprising the structure —B(R^(9′))₂(I_(m)), wherein I_(m) is animaging moiety, optionally ¹⁸F.

Embodiment 168

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-165, wherein the at least one imaging moiety is associated with agroup comprising the structure —Si(R⁹)₂(I_(m)), wherein I_(m) is animaging moiety, optionally ¹⁸F.

Embodiment 169

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-168, wherein all but one R⁶ is H.

Embodiment 170

The compound of embodiment 169, wherein one R⁶ is substituted with theat least one imaging moiety.

Embodiment 171

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is alkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, eachsubstituted with an imaging moiety.

Embodiment 172

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —O(CH₂)_(j)I_(m); wherein I_(m) isan imaging moiety and j is 1, 2, 3, 4, 5, or 6.

Embodiment 173

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —(CH₂)_(j)O(CH₂)_(j)I_(m); whereinI_(m) is an imaging moiety and each j is independently 1, 2, 3, 4, 5, or6.

Embodiment 174

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —C≡C—(CH₂)_(j)I_(m); wherein I_(m)is an imaging moiety and j is 1, 2, 3, 4, 5, or 6.

Embodiment 175

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6.

Embodiment 176

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —O[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m);wherein I_(m) is an imaging moiety and each j is independently 1, 2, 3,4, 5, or 6.

Embodiment 177

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is optionally substituted alkylsubstituted with an imaging moiety.

Embodiment 178

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —C(═O)O(CH₂)_(j)I_(m); wherein I_(m)is an imaging moiety and j is 1, 2, 3, 4, 5, or 6.

Embodiment 179

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —C(═O)(CH₂)_(j)I_(m); wherein I_(m)is an imaging moiety and j is 1, 2, 3, 4, 5, or 6.

Embodiment 180

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —(CH₂)_(j)NH(CH₂)_(j)I_(m); whereinI_(m) is an imaging moiety and each j is independently 1, 2, 3, 4, 5, or6.

Embodiment 181

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is Si(R⁹)₂I_(m), wherein each R⁹ isalkyl optionally substituted and wherein I_(m) is an imaging moiety.

Embodiment 182

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein the at least one imaging moiety is associated with agroup comprising the structure —B(R^(9′))₂(I_(m)), wherein I_(m) is animaging moiety, optionally ¹⁸F.

Embodiment 183

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is selected from the group consistingof —C≡C—CH₂CH₂CH₂I_(m), —C≡C—CH₂CH₂I_(m), —C≡C—CH₂I_(m), —CH₂I_(m),—(CH₂)₂I_(m), —(CH₂)₃I_(m), —(CH₂)₄I_(m), —(CH₂)₅I_(m), —(CH₂)₆I_(m),—OCH₂I_(m), —O(CH₂)₂I_(m), —O(CH₂)₃I_(m), —O(CH₂)₄I_(m), —O(CH₂)₅I_(m),—O(CH₂)₆I_(m), —CH₂O(CH₂)₂I_(m), —CH(CH₃)O(CH₂)₂I_(m), —CH₂O(CH₂)₃I_(m),—CD₂O(CH₂)₂I_(m), —(CH₂)₂O(CH₂)₂I_(m), —CHBrC(CH₃)₂I_(m),—CHClC(CH₃)₂I_(m), —CHFC(CH₃)₂I_(m), —C(═O)OCH₂I_(m),—C(═O)O(CH₂)₂I_(m), —C(═O)O(CH₂)₃I_(m), —CH₂NH(CH₂)₂I_(m),—CH₂NHCH₂I_(m), —CH₂O(CH₂)₂O(CH₂)₂I_(m), —CH₂O(CH₂)₂O(CH₂)₃I_(m),—O(CH₂)₂O(CH₂)₂I_(m), —C(═O)(CH₂)₂I_(m), and —C(═O)(CH₂)₃I_(m);optionally, wherein I_(m) is ¹⁸F.

Embodiment 184

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is an imaging moiety, optionally,wherein the imaging moiety is ¹⁸F.

Embodiment 185

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is optionally substituted with at leastone ²H.

Embodiment 186

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —Si(R⁹)₃.

Embodiment 187

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-166, wherein at least one R⁶ is —B(R^(9′))₃.

Embodiment 188

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-187, wherein at least one R⁶ is —NO₂.

Embodiment 189

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-187, wherein at least one R⁶ is halo.

Embodiment 190

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-187, wherein at least one R⁶ is C1.

Embodiment 191

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-187, wherein at least one R⁶ is Br.

Embodiment 192

The compound of any one of embodiments 1-13, 15-70, 72-124, 132-161, and163-187, wherein at least one R⁶ is F.

Embodiment 193

In embodiment 193, provided is a compound comprising the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R²⁰ is selected from the group consisting of hydrogen, heteroalkyloptionally substituted, alkoxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —CN, and —NO₂;

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and an imaging moiety, or optionally anytwo R²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted; G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one imaging moiety is present in the compound.

Embodiment 194

In embodiment 194, provided is a compound comprising the formula:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R²¹ and R²³ is independently selected from the group        consisting of hydrogen, alkyl optionally substituted,        heteroalkyl optionally substituted, alkoxy optionally        substituted, alkoxyalkyl optionally substituted, halo,        haloalkyl, and an imaging moiety, or optionally any two R²¹ or        any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and animaging moiety;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and an imaging moiety;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and an imaging moiety, or optionally, any two R⁷ may bejoined together to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and an imaging moiety;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and an imaging moiety;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and animaging moiety;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

R²⁹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, optionally substitutedalkoxy, optionally substituted alkoxyalkyl, halo, haloalkyl, —CN, —NO₂,and an imaging moiety; G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted, provided at least one K isalkenylene, or alkynylene;

each b is independently 0, 1, 2, 3, or 4; and cis 1 or 2,

provided at least one imaging moiety is present in the compound.

Embodiment 195

The compound of embodiment 193, wherein R²⁹ is alkyl optionallysubstituted.

Embodiment 196

The compound of embodiment 193, wherein R²⁹ is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl.

Embodiment 197

The compound of embodiment 193, wherein R²⁹ is methyl.

Embodiment 198

The compound of embodiment 194, wherein the compound comprises thestructure:

Embodiment 199

The compound of embodiment 193, wherein the compound comprises thestructure:

Embodiment 200

The compound of any one of embodiments 193-199, wherein each of R²⁴,R²⁵, R²⁶, and R²⁷ are H.

Embodiment 201

The compound of any one of embodiments 193-200, wherein G is O.

Embodiment 202

The compound of any one of embodiments 193-200, wherein G is S.

Embodiment 203

The compound of any one of embodiments 193-200, wherein G is NR².

Embodiment 204

The compound of any one of embodiments 193-200, wherein G is NH.

Embodiment 205

The compound of any one of embodiments 193-204, wherein a is 0.

Embodiment 206

The compound of any one of embodiments 193-204, wherein a is 1.

Embodiment 207

The compound of any one of embodiments 193-204, wherein a is 2.

Embodiment 208

The compound of any one of embodiments 193-204, wherein a is 3.

Embodiment 209

The compound of any one of embodiments 193-204, wherein a is 4.

Embodiment 210

The compound of any one of embodiments 193-197 or 200-209, wherein atleast one K is alkynylene.

Embodiment 211

The compound of any one of embodiments 193-197 or 200-209, wherein

has the structure:

wherein each e is independently 1, 2, 3, or 4.

Embodiment 212

The compound of any one of embodiments 193-211, wherein each R²¹ is H.

Embodiment 213

The compound of any one of embodiments 193-212, wherein R²² is—O(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and j is 1, 2, 3,4, 5, or 6.

Embodiment 214

The compound of any one of embodiments 193-212, wherein R²² is—(CH₂)_(j)O(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety and each jis independently 1, 2, 3, 4, 5, or 6.

Embodiment 215

The compound of any one of embodiments 193-212, wherein R²² is—[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety andeach j is independently 1, 2, 3, 4, 5, or 6.

Embodiment 216

The compound of any one of embodiments 193-212, wherein R²² is—O[(CH₂)_(j)O]_(j)(CH₂)_(j)I_(m); wherein I_(m) is an imaging moiety andeach j is independently 1, 2, 3, 4, 5, or 6.

Embodiment 217

The compound of any one of embodiments 193-212, wherein R²² isoptionally substituted alkyl substituted with an imaging moiety.

Embodiment 218

The compound of any one of embodiments 193-212, wherein the at least oneimaging moiety is present in R²¹, R²², R², R²⁴, R², R²⁶, or R⁷.

Embodiment 219

The compound of any one of embodiments 193-212, wherein the at least oneimaging moiety is present in R²¹, R²², R², R²⁴, R²⁵, R²⁶, R²⁷ or R²⁹.

Embodiment 220

The compound of any one of embodiments 193-212, wherein the at least oneimaging moiety is present in R²¹, R²², or R²⁹.

Embodiment 221

The compound of any one of embodiments 193-212, wherein the at least oneimaging moiety is present in R²².

Embodiment 222

The compound of any one of embodiments 193-212, wherein R²² comprisesthe at least one imaging moiety.

Embodiment 223

The compound of any one of embodiments 193-212, wherein R²² is animaging moiety.

Embodiment 224

The compound of any one of embodiments 193-223, wherein the at least oneimaging moiety is selected from the group consisting of ¹¹C, ¹³N, ¹⁸F,⁷⁶Br, ⁸⁹Zr, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu,⁶⁷Ga, and ⁶⁸Ga.

Embodiment 225

The compound of any one of embodiments 193-224, wherein the at least oneimaging moiety is ¹⁸F.

Embodiment 226

The compound of embodiment 194, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof, wherein F is optionally¹⁸F.

Embodiment 227

In embodiment 227, provided is a compound is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof, wherein I_(m) is animaging moiety.

Embodiment 228

The compound of embodiment 227, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof, wherein each F isoptionally ¹⁸F.

Embodiment 229

In embodiment 229, provided is a compound selected from the group

or a pharmaceutically acceptable salt thereof, wherein I_(m) is animaging moiety.

Embodiment 230

The compound of embodiment 229, wherein the compound is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof, wherein each F isoptionally ¹⁸F.

Embodiment 231

In embodiment 231, provided is a pharmaceutical composition comprising acompound or a salt thereof of any preceding embodiment, and optionally apharmaceutically acceptable excipient.

Embodiment 232

In embodiment 232, provided is a sterile aqueous solution comprising acompound or a salt thereof of any preceding embodiment.

Embodiment 233

Use of a compound or a salt thereof of any preceding embodiment as animaging agent.

Embodiment 234

Use of a compound or a salt thereof of any preceding embodiment inmyocardial perfusion imaging.

Embodiment 235

Use of a compound or salt thereof of any preceding embodiment in themanufacture of a medicament for detecting, imaging or monitoringmyocardial perfusion.

Embodiment 236

In embodiment 236, provided is a method of imaging a portion of asubject, comprising:

administering to the subject a compound or a salt thereof of anypreceding embodiment, or a composition of embodiment 231, or a sterileaqueous solution of embodiment 232; and

acquiring at least one image of a portion of the subject.

Embodiment 237

In embodiment 237, provided is a method of imaging a portion of asubject, comprising:

administering to a subject a compound or a salt thereof of any precedingembodiment or a salt thereof, or a pharmaceutical composition ofembodiment 231, or a sterile aqueous solution of embodiment 232;

detecting radiation emitted by the compound; and

forming an image therefrom.

Embodiment 238

The method of embodiment 237, wherein the portion of the subject imagedis a portion of the heart.

Embodiment 239

In embodiment 239, provided is a diagnostic kit comprising one or morevials containing a precursor to a compound or a salt thereof of anypreceding embodiment; and optionally other components.

Embodiment 240

The diagnostic kit of embodiment 239, wherein the diagnostic kit is forthe preparation of diagnostic agents for imaging, detecting, and/ormonitoring myocardial perfusion in a subject.

Embodiment 241

The diagnostic kit of embodiment 239 or 240, wherein said othercomponents are selected from the group consisting of ancillary ligands,reducing agents, transfer ligands, buffers, lyophilization aids,stabilization aids, solubilization aids, and bacteriostats.

Embodiment 242

In embodiment 242, provided is a method of imaging myocardial perfusion,comprising:

administering to a patient a compound or a salt thereof of any precedingembodiment, or a pharmaceutical composition of embodiment 231, or asterile aqueous solution of embodiment 232; and

scanning the patient using diagnostic imaging.

Embodiment 243

In embodiment 243, provided is a method of detecting myocardialperfusion, comprising:

administering to a patient a compound or a salt thereof of any precedingembodiment, or a pharmaceutical composition of embodiment 231, or asterile aqueous solution of embodiment 232; and

scanning the patient using diagnostic imaging.

Embodiment 244

In embodiment 244, provided is a method of monitoring myocardialperfusion, comprising:

administering to a patient a compound or a salt thereof of any precedingembodiment, or a pharmaceutical composition of embodiment 231, or asterile aqueous solution of embodiment 232; and

scanning the patient using diagnostic imaging.

Embodiment 245

In embodiment 245, provided is a compound comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, heterocyclyl or aryl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound; and

provided that when W is aryl, a) R³ is not halo, alkyl or haloalkyl, orb) at least one R⁶ is selected from the group consisting of alkynyloptionally substituted, alkenyl optionally substituted, alkylsubstituted with —CN, alkyl substituted with —C(═O)OR⁸, alkylsubstituted with —C(═O)R⁸, alkyl substituted with —N(R⁷)₂, —CN, —NO₂,—N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸, —C(═O)R⁸, —C(═O)N(R⁷)₂, and—N(R⁷)C(═O)R⁸.

Embodiment 246

The compound of embodiment 245, wherein the compound comprises thestructure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

W is heteroaryl, naphthyl, or heterocyclyl;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 247

The compound of embodiment 245, wherein the compound comprises thestructure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

Q has the structure:

each Y and each X is independently selected from the group consisting ofC, C(R⁶), C(R⁶)₂, N, NR⁷, O, and S, provided at least one Y is not C orC(R⁶);

each

is independently a single or double bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; each R⁸ is independently selected from thegroup consisting of hydrogen, alkyl optionally substituted, heteroalkyloptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, haloalkyl,and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 248

The compound of embodiment 245, wherein the compound comprises thestructure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, unsubstitutedalkyl or alkyl optionally substituted with a moiety other than ahalogen, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, —CN, and —NO₂;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, or 5;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 249

In embodiment 249, provided is a compound comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

each R⁴, R⁵, and R¹¹ is independently selected from the group consistingof hydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

q, and r are each independently 0, 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 250

In embodiment 250, provided is a compound comprising the structure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, —NO₂, haloalkyl,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of N(R⁷), S, O, C(═O), C(═O)O,OC(═O), C(═O)N(R⁷)₂, N(R⁷)C(═O), and —CH₂O;

each R⁴ and R⁵ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ or any two of R⁵ are joined together to form aring;

n is 1, 2, or 3;

Z is selected from the group consisting of aryl, heteroaryl,heterocyclyl, and a bond;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

m is 0, 1, 2, 3, 4, 5, 6, or 7;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 251

The compound of embodiment 245, wherein the compound comprises thestructure:

or a salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, and a leaving group;

R² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —NO₂,and a leaving group;

R³ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxy optionallysubstituted, alkoxyalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —CN,—NO₂, and a leaving group;

J is selected from the group consisting of consisting of N(R⁷), S, O,C(═O), C(═O)O, OC(═O), C(═O)N(R⁷), N(R⁷)C(═O), CH₂O, and a bond;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl optionally substituted, and a leaving group, oroptionally any two of R⁴ and R⁵ are joined together to form a ring;

n is 0, 1, 2, or 3;

each R⁶ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, aryloxy optionally substituted, heteroaryloxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, —N(R⁷)₂, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸, —OC(═O)R⁸,—C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, —Si(R⁹)₃, —B(R^(9′))₃, —OR⁸, and aleaving group;

p is 0, 1, 2, 3, or 4;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

R¹² is selected from the group consisting of alkynyl optionallysubstituted, alkenyl optionally substituted, alkyl substituted with —CN,alkyl substituted with —C(═O)OR⁸, alkyl substituted with —C(═O)R⁸, alkylsubstituted with —N(R⁷)₂, —CN, —NO₂, —N(R⁷)₂, —C(═O)OR⁸. —OC(═O)R⁸,—C(═O)R⁸, —C(═O)N(R⁷)₂, and —N(R⁷)C(═O)R⁸;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group; and

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup,

provided that at least one leaving group is present in the compound.

Embodiment 252

In embodiment 252, provided is a compound comprising the formula:

or a salt thereof, wherein:

R²⁰ is selected from the group consisting of hydrogen, heteroalkyloptionally substituted, alkoxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —CN, and —NO₂;

each R²¹ and R²³ is independently selected from the group consisting ofhydrogen, alkyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, and a leaving group, or optionally any twoR²¹ or any two R²³ may be joined together to form a ring;

R²² is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, alkoxyalkyl optionallysubstituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃, —B(R^(9′))₃, and aleaving group;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and a leaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring; each R⁸ is independently selected from thegroup consisting of hydrogen, alkyl optionally substituted, heteroalkyloptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, haloalkyl,and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one leaving group is present in the compound.

Embodiment 253

In embodiment 253, provided is a compound comprising the formula:

or a salt thereof, wherein:

-   -   each R²¹ and R²³ is independently selected from the group        consisting of hydrogen, alkyl optionally substituted,        heteroalkyl optionally substituted, alkoxy optionally        substituted, alkoxyalkyl optionally substituted, halo,        haloalkyl, and a leaving group, or optionally any two R²¹ or any        two R²² may be joined together to form a ring; R²² is selected        from the group consisting of hydrogen, alkyl optionally        substituted, heteroalkyl optionally substituted, alkoxyalkyl        optionally substituted, halo, haloalkyl, —OR²⁸, —Si(R⁹)₃,        —B(R^(9′))₃, and a leaving group;

R²⁴, R²⁵, R²⁶, and R²⁷ are each independently selected from the groupconsisting of hydrogen, alkyl optionally substituted, alkenyl optionallysubstituted, alkynyl optionally substituted, heteroalkyl optionallysubstituted, alkoxy optionally substituted, aryloxy optionallysubstituted, heteroaryloxy optionally substituted, alkoxyalkyloptionally substituted, aryl optionally substituted, heteroaryloptionally substituted, halo, haloalkyl, —NO₂, —OH, —C(═O)R⁸, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)N(R⁷)₂, —N(R⁷)C(═O)R⁸, —CN, and a leaving group;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, alkenyl optionally substituted, alkynyloptionally substituted, heteroalkyl optionally substituted, alkoxyoptionally substituted, alkoxyalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, halo,haloalkyl, and a leaving group, or optionally, any two R⁷ may be joinedtogether to form a ring;

each R⁸ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, heteroalkyl optionally substituted,alkoxyalkyl optionally substituted, aryl optionally substituted,heteroaryl optionally substituted, haloalkyl, and a leaving group;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl optionally substituted, aryl optionally substituted, haloalkyl,halogen, and a leaving group;

each R^(9′) is independently selected from the group consisting of halo,alkyl optionally substituted, aryl optionally substituted, and a leavinggroup;

R²⁸ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, and heteroalkyl optionally substituted;

R²⁹ is selected from the group consisting of hydrogen, alkyl optionallysubstituted, heteroalkyl optionally substituted, aryl optionallysubstituted, heteroaryl optionally substituted, halo, haloalkyl, —C,—NO₂, and a leaving group;

G is O, S, or NR²⁸;

a is 0, 1, 2, 3, or 4;

each K is independently arylene, heteroarylene, alkenylene, oralkynylene, each optionally substituted, provided at least one K isalkenylene, or alkynylene;

each b is independently 0, 1, 2, 3, or 4; and

c is 1 or 2,

provided at least one leaving group is present in the compound.

Embodiment 254

In embodiment 254, provided is a diagnostic kit comprising one or morevials containing a compound of any one of embodiments 245-253 or a saltthereof; and optionally other components.

Embodiment 255

The diagnostic kit of embodiment 254, wherein the diagnostic kit is forthe preparation of diagnostic agents for imaging, detecting, and/ormonitoring myocardial perfusion in a subject.

Embodiment 256

The diagnostic kit of embodiment 254 or 255, wherein said othercomponents are selected from the group consisting of ancillary ligands,reducing agents, transfer ligands, buffers, lyophilization aids,stabilization aids, solubilization aids, and bacteriostats.

Embodiment 257

In embodiment 257, provided is a method for forming an imaging agent,comprising reacting a compound of any one of embodiments 245-253 or asalt thereof with an ¹⁸F-containing species to produce a imaging agentcomprising ¹⁸F.

Embodiment 258

In embodiment 258, provided is a cassette for the preparation of animaging agent comprising the components arranged as shown in FIG. 17 .

Embodiment 259

The cassette as in embodiment 258, wherein the imaging agent has theformula:

Embodiment 260

In embodiment 260, provided is an apparatus for synthesizing an imagingagent comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order:

-   -   1) luer connections (2) to gas inlet and [18O]H2O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) spike connection for acetonitrile;    -   4) empty syringe;    -   5) reservoir with solution of imaging agent precursor;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) syringe with solution of a stabilizing agent;    -   12) syringe with water;    -   13) final product vial;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

Embodiment 261

In embodiment 261, provided is an apparatus for synthesizing an imagingagent comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order:

-   -   1) luer connections (2) to gas inlet and [18O]H2O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) reservoir with solution of imaging agent precursor;    -   4) empty syringe;    -   5) spike connection for acetonitrile;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) syringe with solution of a stabilizing agent;    -   12) syringe with water,    -   13) final product vial;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

Embodiment 262

In embodiment 262, provided is an apparatus for synthesizing an imagingagent comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order:

-   -   1) luer connections (2) to gas inlet and [18O]H2O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) reservoir with solution of imaging agent precursor;    -   4) empty syringe;    -   5) spike connection for acetonitrile;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) final product vial;    -   12) syringe with water    -   13) syringe with solution of a stabilizing agent    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

Embodiment 263

In embodiment 263, provided is an apparatus for synthesizing an imagingagent comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order:

-   -   1) luer connections (2) to gas inlet and [18O]H2O recovery;    -   2) anion exchange cartridge—column eluting solution;    -   3) spike connection for acetonitrile;    -   4) empty syringe;    -   5) reservoir with solution of imaging agent precursor;    -   6) reaction vessel;    -   7) outlet to HPLC;    -   8) syringe with solution of a stabilizing agent;    -   9) inlet from HPLC;    -   10) ethanol reservoir;    -   11) final product vial;    -   12) syringe with water;    -   13) syringe with solution of a stabilizing agent;    -   14) empty syringe; and    -   15) reaction vessel and exhaust.

Embodiment 264

The apparatus of any one of embodiments 260-263, further comprisingtubing.

Embodiment 265

The apparatus of any one of embodiments 260-264, further comprising animaging agent synthesis module, wherein the apparatus is fluidicallyconnected to the apparatus.

Embodiment 266

The apparatus of any one of embodiments 260-265, wherein the apparatusis capable of preparing an imaging agent comprising the formula:

Embodiment 267

The apparatus of any one of embodiments 260-266, wherein the solution ofa stabilizing agent comprises a solution comprising ascorbic acid or asalt thereof.

Embodiment 268

The apparatus of any one of embodiments 267, wherein the syringe withsolution of ascorbic acid or salt thereof at position 8 comprises asolution of ascorbic acid at pH 2.

Embodiment 269

The apparatus of any one of embodiments 260-268, wherein the syringewith solution of ascorbic acid or salt thereof at position 11 comprisesa solution of ascorbic acid at pH 5.8.

Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are listed here.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(h)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, the entire contents of which are incorporatedherein by reference.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

Isomeric mixtures containing any of a variety of isomer ratios may beutilized in accordance with the present invention. For example, whereonly two isomers are combined, mixtures containing 50:50, 60:40, 70:30,80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios areall contemplated by the present invention. Those of ordinary skill inthe art will readily appreciate that analogous ratios are contemplatedfor more complex isomer mixtures.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The term “aliphatic,” as used herein, includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, and cyclic (i.e., carbocyclic) hydrocarbons, which areoptionally substituted with one or more functional groups. As will beappreciated by one of ordinary skill in the art, “aliphatic” is intendedherein to include, but is not limited to, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as usedherein, the term “alkyl” includes straight, branched and cyclic alkylgroups. An analogous convention applies to other generic terms such as“alkenyl”, “alkynyl”, and the like. Furthermore, as used herein, theterms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass bothsubstituted and unsubstituted groups. In certain embodiments, as usedherein, “aliphatic” is used to indicate those aliphatic groups (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. Aliphatic group substituents include, but are not limitedto, any of the substituents described herein, that result in theformation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl,heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino,thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo,aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino,arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which mayor may not be further substituted).

As used herein, the term “alkyl” is given its ordinary meaning in theart and refers to the radical of saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkylsubstituted alkyl groups. In some cases, the alkyl group may be a loweralkyl group, i.e., an alkyl group having 1 to 10 carbon atoms (e.g.,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, ordecyl). In some embodiments, a straight chain or branched chain alkylmay have 30 or fewer carbon atoms in its backbone, and, in some cases,20 or fewer. In some embodiments, a straight chain or branched chainalkyl may have 12 or fewer carbon atoms in its backbone (e.g., C₁-C₁₂for straight chain, C₃-C₁₂ for branched chain), 6 or fewer, or 4 orfewer. Likewise, cycloalkyls may have from 3-10 carbon atoms in theirring structure, or 5, 6 or 7 carbons in the ring structure. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, hexyl, andcyclochexyl.

The term “alkylene” as used herein refers to a bivalent alkyl group. An“alkylene” group is a polymethylene group, i.e., —(CH₂)_(z)—, wherein zis a positive integer, e.g., from 1 to 20, from 1 to 10, from 1 to 6,from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substitutedalkylene chain is a polymethylene group in which one or more methylenehydrogen atoms are replaced with a substituent. Suitable substituentsinclude those described herein for a substituted aliphatic group.

Generally, the suffix “-ene” is used to describe a bivalent group. Thus,any of the terms defined herein can be modified with the suffix “-ene”to describe a bivalent version of that moiety. For example, a bivalentcarbocycle is “carbocyclylene”, a bivalent aryl ring is “arylene”, abivalent benzene ring is “phenylene”, a bivalent heterocycle is“heterocyclylene”, a bivalent heteroaryl ring is “heteroarylene”, abivalent alkyl chain is “alkylene”, a bivalent alkenyl chain is“alkenylene”, a bivalent alkynyl chain is “alkynylene”, a bivalentheteroalkyl chain is “heteroalkylene”, a bivalent heteroalkenyl chain is“heteroalkenylene”, a bivalent heteroalkynyl chain is“heteroalkynylene”, and so forth.

The terms “alkenyl” and “alkynyl” are given their ordinary meaning inthe art and refer to unsaturated aliphatic groups analogous in lengthand possible substitution to the alkyls described above, but thatcontain at least one double or triple bond respectively.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1-10 aliphatic carbon atoms.

In yet other embodiments, the alkyl, alkenyl, and alkynyl groupsemployed in the invention contain 1-8 aliphatic carbon atoms. In stillother embodiments, the alkyl, alkenyl, and alkynyl groups employed inthe invention contain 1-6 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1-4 carbon atoms. Illustrative aliphatic groups thusinclude, but are not limited to, for example, methyl, ethyl, n-propyl,isopropyl, allyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl,sec-pentyl, isopentyl, t-pentyl, n-hexyl, sec-hexyl, moieties and thelike, which again, may bear one or more substituents. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynylgroups include, but are not limited to, ethynyl, 2-propynyl (propargy1), 1-propynyl and the like.

The term “cycloalkyl,” as used herein, refers specifically to groupshaving three to ten, preferably three to seven carbon atoms. Suitablecycloalkyls include, but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the caseof other aliphatic, heteroaliphatic, or hetercyclic moieties, mayoptionally be substituted with substituents including, but not limitedto aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl;heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I;—OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R;—OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x), wherein eachoccurrence of R_(x) independently includes, but is not limited to,aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein any of the aliphatic, heteroaliphatic,arylalkyl, or heteroarylalkyl substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and wherein any of the aryl or heteroaryl substituentsdescribed above and herein may be substituted or unsubstituted.Additional examples of generally applicable substitutents areillustrated by the specific embodiments shown in the Examples that aredescribed herein.

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety, as defined herein, which includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, cyclic (i.e., heterocyclic), or polycyclic hydrocarbons, whichare optionally substituted with one or more functional groups, and thatcontain one or more oxygen, sulfur, nitrogen, phosphorus, or siliconatoms, e.g., in place of carbon atoms. In certain embodiments,heteroaliphatic moieties are substituted by independent replacement ofone or more of the hydrogen atoms thereon with one or more substituents.As will be appreciated by one of ordinary skill in the art,“heteroaliphatic” is intended herein to include, but is not limited to,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. Thus, the term“heteroaliphatic” includes the terms “heteroalkyl,” “heteroalkenyl”,“heteroalkynyl”, and the like. Furthermore, as used herein, the terms“heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompassboth substituted and unsubstituted groups. In certain embodiments, asused herein, “heteroaliphatic” is used to indicate those heteroaliphaticgroups (cyclic, acyclic, substituted, unsubstituted, branched orunbranched) having 1-20 carbon atoms. Heteroaliphatic group substituentsinclude, but are not limited to, any of the substituents describedherein, that result in the formation of a stable moiety (e.g.,aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano,isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino,heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy,alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy,heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy,heteroarylthioxy, acyloxy, and the like, each of which may or may not befurther substituted).

The term “heteroalkyl” is given its ordinary meaning in the art andrefers to an alkyl group as described herein in which one or more carbonatoms is replaced by a heteroatom. Suitable heteroatoms include oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of heteroalkylgroups include, but are not limited to, alkoxy, alkoxyalkyl, amino,thioester, poly(ethylene glycol), and alkyl-substituted amino.

The terms “heteroalkenyl” and “heteroalkynyl” are given their ordinarymeaning in the art and refer to unsaturated aliphatic groups analogousin length and possible substitution to the heteroalkyls described above,but that contain at least one double or triple bond respectively.

Some examples of substituents of the above-described aliphatic (andother) moieties of compounds of the invention include, but are notlimited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl;alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH;—NO₂; —CN; —CF₃; —CHF₂; —CH₂F; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,heteroaliphatic, alkylaryl, or alkylheteroaryl substituents describedabove and herein may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and wherein any of the aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

The term “aryl” is given its ordinary meaning in the art and refers toaromatic carbocyclic groups, optionally substituted, having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fusedrings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). That is,at least one ring may have a conjugated pi electron system, while other,adjoining rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls. The aryl group may be optionally substituted, asdescribed herein. Substituents include, but are not limited to, any ofthe previously mentioned substitutents, i.e., the substituents recitedfor aliphatic moieties, or for other moieties as disclosed herein,resulting in the formation of a stable compound. In some cases, an arylgroup is a stable mono- or polycyclic unsaturated moiety havingpreferably 3-14 carbon atoms, each of which may be substituted orunsubstituted. “Carbocyclic aryl groups” refer to aryl groups whereinthe ring atoms on the aromatic ring are carbon atoms. Carbocyclic arylgroups include monocyclic carbocyclic aryl groups and polycyclic orfused compounds (e.g., two or more adjacent ring atoms are common to twoadjoining rings) such as naphthyl groups.

The terms “heteroaryl” is given its ordinary meaning in the art andrefers to aryl groups comprising at least one heteroatom as a ring atom.A “heteroaryl” is a stable heterocyclic or polyheterocyclic unsaturatedmoiety having preferably 3-14 carbon atoms, each of which may besubstituted or unsubstituted. Substituents include, but are not limitedto, any of the previously mentioned substitutents, i.e., the substitutesrecited for aliphatic moieties, or for other moieties as disclosedherein, resulting in the formation of a stable compound. In some cases,a heteroaryl is a cyclic aromatic radical having from five to ten ringatoms of which one ring atom is selected from S, O, and N; zero, one, ortwo ring atoms are additional heteroatoms independently selected from S,O, and N; and the remaining ring atoms are carbon, the radical beingjoined to the rest of the molecule via any of the ring atoms, such as,for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

It will also be appreciated that aryl and heteroaryl moieties, asdefined herein may be attached via an alkyl or heteroalkyl moiety andthus also include -(alkyl)aryl, -(heteroalkyl)aryl,-(heteroalkyl)heteroaryl, and -(heteroalkyl)heteroaryl moieties. Thus,as used herein, the phrases “aryl or heteroaryl moieties” and “aryl,heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl,and -(heteroalkyl)heteroaryl” are interchangeable. Substituents include,but are not limited to, any of the previously mentioned substituents,i.e., the substituents recited for aliphatic moieties, or for othermoieties as disclosed herein, resulting in the formation of a stablecompound.

It will be appreciated that aryl and heteroaryl groups (includingbicyclic aryl groups) can be unsubstituted or substituted, whereinsubstitution includes replacement of one or more of the hydrogen atomsthereon independently with any one or more of the following moietiesincluding, but not limited to: aliphatic; alicyclic; heteroaliphatic;heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl;heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy;aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO₂; —CN; —CF₃;—CH₂F; —CHF₂; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃;—C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R_(x);—OCON(R_(x))₂; —N(R_(x))₂; —S(O)R_(x); —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl, heteroaryl,-(alkyl)aryl or -(alkyl)heteroaryl substituents described above andherein may be substituted or unsubstituted. Additionally, it will beappreciated, that any two adjacent groups taken together may represent a4, 5, 6, or 7-membered substituted or unsubstituted alicyclic orheterocyclic moiety. Additional examples of generally applicablesubstituents are illustrated by the specific embodiments describedherein.

The term “heterocycle” is given its ordinary meaning in the art andrefers to cyclic groups containing at least one heteroatom as a ringatom, in some cases, 1 to 3 heteroatoms as ring atoms, with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude oxygen, sulfur, nitrogen, phosphorus, and the like. In somecases, the heterocycle may be 3- to 10-membered ring structures or 3- to7-membered rings, whose ring structures include one to four heteroatoms.

The term “heterocycle” may include heteroaryl groups, saturatedheterocycles (e.g., cycloheteroalkyl) groups, or combinations thereof.The heterocycle may be a saturated molecule, or may comprise one or moredouble bonds. In some cases, the heterocycle is a nitrogen heterocycle,wherein at least one ring comprises at least one nitrogen ring atom. Theheterocycles may be fused to other rings to form a polycylicheterocycle. The heterocycle may also be fused to a spirocyclic group.In some cases, the heterocycle may be attached to a compound via anitrogen or a carbon atom in the ring.

Heterocycles include, for example, thiophene, benzothiophene,thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole,pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, oxazine, piperidine, homopiperidine(hexamethyleneimine), piperazine (e.g., N-methyl piperazine),morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, other saturated and/or unsaturated derivativesthereof, and the like. The heterocyclic ring can be optionallysubstituted at one or more positions with such substituents as describedherein.

In some cases, the heterocycle may be bonded to a compound via aheteroatom ring atom (e.g., nitrogen). In some cases, the heterocyclemay be bonded to a compound via a carbon ring atom. In some cases, theheterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine,acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline,benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or thelike.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom the group consisting of fluorine, chlorine, bromine, and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “amino,” as used herein, refers to a primary (—NH₂), secondary(—NHR_(x)), tertiary (—NR_(x)R_(y)), or quaternary (—N⁺R_(x)R_(y)R_(z))amine, where R_(x), R_(y), and R_(z) are independently an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety, asdefined herein. Examples of amino groups include, but are not limitedto, methylamino, dimethylamino, ethylamino, diethylamino,methylethylamino, iso-propylamino, piperidino, trimethylamino, andpropylamino.

The term “alkyne” is given its ordinary meaning in the art and refers tobranched or unbranched unsaturated hydrocarbon groups containing atleast one triple bond. Non-limiting examples of alkynes includeacetylene, propyne, 1-butyne, 2-butyne, and the like. The alkyne groupmay be substituted and/or have one or more hydrogen atoms replaced witha functional group, such as a hydroxyl, halogen, alkoxy, and/or arylgroup.

The term “alkoxy” (or “alkyloxy”), or “thioalkyl” as used herein refersto an alkyl group, as previously defined, attached to the parentmolecular moiety through an oxygen atom or through a sulfur atom. Incertain embodiments, the alkyl group contains 1-20 aliphatic carbonatoms. In certain other embodiments, the alkyl group contains 1-10aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 1-8 aliphaticcarbon atoms. In still other embodiments, the alkyl group contains 1-6aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but arenot limited to, methoxy, ethoxy,

propoxy, isopropoxy, n-butoxy, t-butoxy, neopentoxy and n-hexoxy.Examples of thioalkyl include, but are not limited to, methylthio,ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

The term “aryloxy” refers to the group, —O-aryl.

The term “acyloxy” refers to the group, —O-acyl.

The term “alkoxyalkyl” refers to an alkyl group substituted with atleast one alkoxy group (e.g., one, two, three, or more, alkoxy groups).For example, an alkoxyalkyl group may be —(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl),optionally substituted. In some cases, the alkoxyalkyl group may beoptionally substituted with another alkyoxyalkyl group (e.g.,—(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl), optionally substituted.

It will be appreciated that the above groups and/or compounds, asdescribed herein, may be optionally substituted with any number ofsubstituents or functional moieties. That is, any of the above groupsmay be optionally substituted. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds, “permissible” being in the context of the chemical rules ofvalence known to those of ordinary skill in the art. In general, theterm “substituted” whether preceeded by the term “optionally” or not,and substituents contained in formulas of this invention, refer to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. When more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. It will be understood that “substituted”also includes that the substitution results in a stable compound, e.g.,which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. In some cases,“substituted” may generally refer to replacement of a hydrogen with asubstituent as described herein. However, “substituted,” as used herein,does not encompass replacement and/or alteration of a key functionalgroup by which a molecule is identified, e.g., such that the“substituted” functional group becomes, through substitution, adifferent functional group. For example, a “substituted phenyl group”must still comprise the phenyl moiety and cannot be modified bysubstitution, in this definition, to become, e.g., a pyridine ring. In abroad aspect, the permissible substituents include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic substituents of organic compounds. Illustrative substituentsinclude, for example, those described herein. The permissiblesubstituents can be one or more and the same or different forappropriate organic compounds. For purposes of this invention, theheteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valencies of the heteroatoms. Furthermore, this invention isnot intended to be limited in any manner by the permissible substituentsof organic compounds. Combinations of substituents and variablesenvisioned by this invention are preferably those that result in theformation of stable compounds useful for the formation of an imagingagent or an imaging agent precursor. The term “stable,” as used herein,preferably refers to compounds which possess stability sufficient toallow manufacture and which maintain the integrity of the compound for asufficient period of time to be detected and preferably for a sufficientperiod of time to be useful for the purposes detailed herein.

Examples of substituents include, but are not limited to, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromaticmoieties, —CF₃, —CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halide,alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido, acyloxy,aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl,-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl,arylalkyloxyalkyl, and the like. In some embodiments, a substituent mayalso be an imaging moiety (e.g., ¹⁸F) or a group for associating animaging moiety (e.g., a chelator). Nitrogen-protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference. Forexample, nitrogen protecting groups include, but are not limited to,carbamates (including methyl, ethyl and substituted ethyl carbamates(e.g., Troc), to name a few), amides, cyclic imide derivatives, N-alkyland N-aryl amines, imine derivatives, and enamine derivatives, to name afew. In some embodiments, the nitrogen-protecting group iscarbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (MeOZ),t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl(Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB),3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), orp-toluenesulfonyloxy (Ts).

Nitrogen-protecting groups such as amide groups include, but are notlimited to, formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen-protecting groups such as carbamate groups include, but are notlimited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate,9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-Boc),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBoc),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (Boc), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen-protecting groups such as sulfonamide groups include, but arenot limited to, p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen-protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

As used herein, the term “determining” generally refers to the analysisof a species or signal, for example, quantitatively or qualitatively,and/or the detection of the presence or absence of the species orsignals.

The term “diagnostic imaging,” as used herein, refers to a procedureused to detect an imaging agent.

The term “diagnosis” as used herein encompasses identification,confirmation, and/or characterization of a condition, a disease, and/ora disorder.

A “diagnostic kit” or “kit” comprises a collection of components, termedthe formulation, in one or more vials which are used by the practicingend user in a clinical or pharmacy setting to synthesize diagnosticradiopharmaceuticals. For example, the kit may be used by the practicingend user in a clinical or pharmacy setting to synthesize and/or usediagnostic radiopharmaceuticals. In some embodiments, the kit mayprovide all the requisite components to synthesize and use thediagnostic pharmaceutical except those that are commonly available tothe practicing end user, such as water or saline for injection and/orthe radioisotope (e.g., ¹⁸F), equipment for processing the kit duringthe synthesis and manipulation of the radiopharmaceutical, if required,equipment necessary for administering the radiopharmaceutical to thesubject such as syringes, shielding, imaging equipment, and the like. Insome embodiments, imaging agents may be provided to the end user intheir final form in a formulation contained typically in one vial orsyringe, as either a lyophilized solid or an aqueous solution.

As used herein, a “portion of a subject” refers to a particular regionof a subject, location of the subject. For example, a portion of asubject may be the brain, heart, vasculature, cardiac vessels, tumor,etc., of a subject.

As used herein a “session” of testing may be a single testing protocolthat a subject undergoes.

As used herein, the term “subject” refers to a human or non-human mammalor animal. Non-human mammals include livestock animals, companionanimals, laboratory animals, and non-human primates. Non-human subjectsalso specifically include, without limitation, horses, cows, pigs,goats, dogs, cats, mice, rats, guinea pigs, gerbils, hamsters, mink, andrabbits. In some embodiments of the invention, a subject is referred toas a “patient.” In some embodiments, a patient or subject may be underthe care of a physician or other health care worker, including, but notlimited to, someone who has consulted with, received advice from orreceived a prescription or other recommendation from a physician orother health care worker.

Any of the compounds described herein may be in a variety of forms, suchas, but not limited to, salts, solvates, hydrates, tautomers, andisomers.

In certain embodiments, the imaging agent is a pharmaceuticallyacceptable salt of the imaging agent. The term “pharmaceuticallyacceptable salt” as used herein refers to those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al., describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66, 1-19, incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from suitable inorganic and organic acids andbases.

Examples of pharmaceutically acceptable, nontoxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counter ions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

In certain embodiments, the compound is in the form of a hydrate orsolvate. The term “hydrate” as used herein refers to a compoundnon-covalently associated with one or more molecules of water. Likewise,the term “solvate” refers to a compound non-covalently associated withone or more molecules of an organic solvent.

In certain embodiments, the compound described herein may exist invarious tautomeric forms. The term “tautomer” as used herein includestwo or more interconvertable compounds resulting from at least oneformal migration of a hydrogen atom and at least one change in valency(e.g., a single bond to a double bond, a triple bond to a single bond,or vice versa). The exact ratio of the tautomers depends on severalfactors, including temperature, solvent, and pH. Tautomerizations (i.e.,the reaction providing a tautomeric pair) may be catalyzed by acid orbase. Exemplary tautomerizations include keto-to-enol; amide-to-imide;lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enaminetautomerizations.

In certain embodiments, the compounds described herein may exist invarious isomeric forms. The term “isomer” as used herein includes anyand all geometric isomers and stereoisomers (e.g., enantiomers,diasteromers, etc.). For example, “isomer” includes cis- andtrans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers,(D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixturesthereof, as falling within the scope of the invention. For instance, anisomer/enantiomer may, in some embodiments, be provided substantiallyfree of the corresponding enantiomer, and may also be referred to as“optically enriched.” “Optically-enriched,” as used herein, means thatthe compound is made up of a significantly greater proportion of oneenantiomer. In certain embodiments the compound of the present inventionis made up of at least about 90% by weight of a preferred enantiomer. Inother embodiments the compound is made up of at least about 95%, 98%, or99% by weight of a preferred enantiomer. Preferred enantiomers may beisolated from racemic mixtures by any method known to those skilled inthe art, including chiral high pressure liquid chromatography (HPLC) andthe formation and crystallization of chiral salts or prepared byasymmetric syntheses. See, for example, Jacques, et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

These and other aspects of the present invention will be furtherappreciated upon consideration of the following Examples, which areintended to illustrate certain particular embodiments of the inventionbut are not intended to limit its scope, as defined by the claims.

EXAMPLES General Experimental Protocols

Method A:

A cooled (0° C.) aqueous solution of mucochloric acid was treated withsodium carbonate in one portion then stirred until complete dissolutionwas observed. The resulting mixture was then treated with thesubstituted hydrazine, and stirred 2.5-5 h while slowly warming toambient temperature. The newly formed precipitate was then collected,exhaustively washed with water, partially dried on the funnel thendissolved in acetic acid and heated to reflux. After 30 min, thesolution was cooled to ambient temperature and all volatiles removed invacuo. The crude pyridazinone was then dissolved in an appropriateorganic solvent, washed with aqueous base, dried, filtered andconcentrated in vacuo. The crude material thus obtained was typicallyused without additional purification, but alternatively may be furtherpurified by chromatography on silica.

Method B:

A solution of the substituted pyridazinone and either a benzylic alcoholor benzylic bromide in dimethylformamide was treated with cesiumcarbonate then optionally heated to 55-80° C. After cooling to ambienttemperature, the crude product was isolated as a solution in ethylacetate, washed with water and aqueous sodium chloride then dried,filtered and concentrated. Subsequent purification by chromatography onsilica afforded the title compound.

Method C:

A dichloromethane solution of the benzylic alcohol was treated withphosphorous tribromide at ambient temperature. After 1-3 h, theresulting mixture was diluted with water and the layers separated. Theaqueous layer was washed with additional dichloromethane, and thecombined extracts dried, filtered and concentrated. The crude materialthus obtained was typically used without additional purification, butalternatively may be further purified by chromatography on silica.

Method D:

A dichloromethane solution of the alcohol, p-toluenesulfonyl chloride,4-dimethylaminopyridine, and a base was prepared at ambient temperature.After 1-3 h, the resulting mixture was diluted with water and the layersseparated. The aqueous layer was washed with additional dichloromethane,and the combined extracts further washed with aqueous sodium chloridethen dried, filtered, and concentrated. Subsequent purification bychromatography on silica afforded the title compound.

Method E:

A suspension of potassium tert-butoxide in 2-fluoroethanol was heated to60° C., maintained 20 min then treated with a solution of the benzylichalide in tetrahydrofuran. The resulting mixture was heated to reflux,maintained 2-24 h then cooled to ambient temperature and treated withwater. The aqueous layer was separated then extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo. Subsequent purification bychromatography on silica afforded the title compound.

Method F:

A suspension of the phenol, 3-fluoropropyl p-toluenesulfonate, andcesium carbonate in dimethylformamide was heated to 60-65° C. andmaintained overnight. After cooling to ambient temperature, theresulting mixture was treated with water, and the aqueous layerextracted with ethyl acetate. The combined organic layers were washedwith water, saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated in vacuo.

Example 1 Preparation of4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-isopropylpyridazin-3(2H)-onePart A—Preparation of 4,5-dichloro-2-isopropylpyridrazin-3(2H)-one

Prepared according to General Method A, using mucochloric acid (1.07 g,6.33 mmol), sodium carbonate (0.336 g, 3.17 mmol), andisopropylhydrazine hydrochloride (0.700 g, 6.33 mmol). Isolatedyield—0.629 g; 47.9%. ¹H NMR (CDCl₃, 300 MHz): δ 7.82 (s, 1H), 5.27 (m,1H), 1.37 (d, J=6.6 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 156.3, 135.9,135.3, 133.8, 51.4, 20.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₇H₈³⁵Cl₂N₂O: 207.0086, found 207.0085.

Part B—Preparation of4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-isopropylpyridazin-3(2H)-one

Prepared according to General Method B, using the product of Example 1A(45.5 mg, 0.220 mmol), (4-((2-fluoroethoxy)methyl)phenyl)methanol (41mg, 0.22 mmol; e.g., see Radeke, H.; Hanson, K.; Yalamanchili, P.;Hayes, M.; Zhang, Z.-Q.; Azure, M.; Yu, M.; Guaraldi, M.; Kagan, M.;Robinson, S.; Casebier, D. Synthesis and Biological evaluation of themitochondrial complex I inhibitor2-[4-(4-fluorobutyl)benzylsulfanyl]-3-methylchromene-4-one as apotential cardiac positron emission tomography tracer. J. Med. Chem.2007, 50, 4304-4315.), and cesium carbonate (0.215 g, 0.661 mmol) indimethylformamide (2.20 mL) at 55° C. Isolated yield—49 mg; 63%. ¹H NMR(CDCl₃, 300 MHz): δ 7.66 (s, 1H), 7.41 (d, J=7.5 Hz, 2H), 7.37 (d, J=8.6Hz, 2H), 5.17 (s, 2H), 4.68 (m, 1H), 4.62 (s, 2H), 4.53 (m, 1H), 3.80(m, 1H), 3.71 (m, 1H), 3.54-3.45 (m, 1H), 1.27 (d, J=7.1 Hz, 6H); ¹³CNMR (CDCl₃, 75 MHz): δ 162.3, 154.2, 138.3, 135.4, 129.3, 128.1, 127.4,125.8, 83.1 (d, J_(CF)=165 Hz), 73.0, 70.8, 69.4 (d, J_(CF)=22.5 Hz),65.0, 19.5; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₇H₂₀ ³⁵ClFN₂O₃:355.1219, found 355.1217.

Example 2 Preparation of2-((4-(((5-chloro-1-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl-4-methylbenzenesulfonate Part A—Preparation of methyl4-(((5-chloro-1-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

Prepared according to General Method B, using the product of Example 1A(0.629 g, 3.01 mmol), 4-hydroxymethyl benzoate (0.550 g, 3.31 mmol), andcesium carbonate (1.57 g, 4.82 mmol) in dimethylformamide (30.0 mL) at60° C. Isolated yield—0.604 g; 59.6%. ¹H NMR (CDCl₃, 300 MHz): δ 8.08(d, J=8.5 Hz, 2H), 7.82 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 5.39 (s, 2H),5.30 (m, 1H), 3.90 (s, 3H), 1.33 (d, J=6.7 Hz, 6H); ¹³C NMR (CDCl₃, 75MHz): δ 166.5, 158.3, 153.6, 139.7, 130.5, 130.2, 129.7, 126.7, 117.5,71.2, 52.0, 50.7, 20.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₇³⁵ClN₂O₄: 337.0950, found 337.0948.

Part B—Preparation of4-chloro-5-((4-(hydroxymethyl)benzyl)oxy)-2-isopropylpyridazin-3(2H)-one

To a solution of the product of Example 2A (0.604 g, 1.79 mmol), intetrahydrofuran at 0° C. was added lithium aluminum hydride (0.9 mL, 0.9mmol, 1 M solution in tetrahydrofuran) dropwise. The resulting mixturewas stirred 3 h then treated with water (20 mL). The aqueous layer wasseparated and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with saturated aqueous sodium chloride (50mL), dried over sodium sulfate, filtered and concentrated to yield anorange solid (0.186 g). ¹H NMR (CDCl₃, 300 MHz): δ 7.82 (s, 1H), 7.41(br s, 4H), 5.32 (s, 2H), 5.28 (m, 1H), 4.72 (s, 2H), 1.28 (d, J=6.7 Hz,6H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.5, 153.8, 141.8, 134.0, 127.5,127.4, 127.0, 117.4, 71.8, 64.8, 50.7, 20.9; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₁₅H₁₇ ³⁵ClN₂O₃: 309.1000, found 309.1001.

Part C—Preparation of5-((4-(bromomethyl)benzyl)oxy)-4-chloro-2-isopropylpyridazin-3(2H)-one

Prepared according to General Method C, using the product of Example 2B(0.186 g, 0.602 mmol) and phosphorous tribromide (0.3 mL, 0.3 mmol, 1 Min dichloromethane). Isolated yield—0.128 g; 57.2%. ¹H NMR (CDCl₃, 300MHz): δ 8.07 (s, 1H), 7.34 (m, 4H), 5.23 (s, 2H), 5.21 (m, 1H), 4.41 (s,2H), 1.24 (d, J=6.6 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.4, 153.7,138.5, 135.0, 129.6, 127.5, 126.9, 117.2, 71.5, 50.7, 32.8, 21.0;HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₅H₁₆ ⁷⁹Br³⁵ClN₂O₂: 371.0156,found 371.0155.

Part D—Preparation of4-chloro-5-((4-((2-hydroxyethoxy)methyl)benzyl)oxy)-2-isopropylpyridazin-3(2H)-one

A suspension of potassium tert-butoxide (48 mg, 0.43 mmol) in ethyleneglycol (0.685 mL) was heated to 60° C. for 30 min. The product ofExample 2C (0.691 g, 1.86 mmol), dissolved in tetrahydrofuran (21.0 mL)was added dropwise. After completion of the addition, the reactionmixture was heated at reflux. After 6 h the reaction mixture was cooledand quenched with water (10 mL). The aqueous layer was separated thenextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by silica gel chromatography (80-100% diethylether in hexanes) to afford the desired product as a white solid (2.8mg, <1% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.76 (br s, 1H), 7.31 (s,4H), 5.23 (s, 2H), 5.19 (m, 1H), 4.48 (s, 2H), 3.67 (m, 2H), 3.52 (m,2H), 1.23 (d, J=6.7 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.4, 153.8,138.9, 134.2, 128.2, 127.3, 127.0, 117.2, 72.7, 71.8, 71.7, 61.8, 50.7,20.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₇₁H₂₁ ³⁵ClN₂O₄: 353.1263,found 353.1267.

Part E—Preparation of2-((4-(((5-chloro-1-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl-4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 2D(85.6 mg, 0.243 mmol), p-toluenesulfonyl chloride (55.6 mg, 0.292 mmol),4-dimethylaminopyridine (35.6 mg, 0.291 mmol), and diisopropylethylamine(0.051 mL, 0.292 mmol). Isolated yield—53 mg; 43%. ¹H (CDCl₃, 300 MHz):δ 7.82 (s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H),7.33-7.27 (m, 4H), 5.31 (s, 2H), 5.28 (m, 1H), 4.51 (s, 2H), 4.20 (m,2H), 3.69 (m, 2H), 2.44 (s, 3H), 1.33 (d, J=6.7 Hz, 6H); ¹³C (CDCl₃, 75MHz): δ 158.4, 153.7, 144.8, 138.5, 134.3, 133.0, 129.8, 128.1, 128.0,127.3, 127.0, 117.4, 72.7, 71.8, 69.2, 67.8, 50.7, 21.7, 20.9; HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₂₄H₂₇ ³⁵ClN₂O₆S: 507.1351, found507.1349.

Example 3 Preparation of 4-chloro-5-((4-((2-fluoroethoxy) methyl)benzyl)oxy)-2-methylpyridazin-3(2H)-one Part A—Preparation of4,5-dichloro-2-methylpyridazin-3(2H)-one

Prepared according to General Method A, using mucochloric acid (2.03 g,12.1 mmol), sodium carbonate (0.640 g, 6.03 mmol), and methyl hydrazine(0.555 g, 12.1 mmol). Isolated yield—0.840 g; 38.8%. ¹H NMR (CDCl₃, 300MHz): δ 7.70 (s, 1H), 3.75 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 156.8,136.5, 135.3, 134.0, 41.0; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₅H₄³⁵Cl₂N₂O: 178.9773, found 178.9773.

Part B—Preparation of4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-methylpyridazin-3(2H)-one

Prepared according to General Method B, using the product of Example 3A(47 mg, 0.26 mmol), (4-((2-fluoroethoxy)methyl)phenyl)methanol (0.141 g,0.770 mmol), and cesium carbonate (0.251 g, 0.770 mmol) indimethylformamide (2.50 mL) at 80° C. Isolated yield—38 mg; 45%. ¹H NMR(CDCl₃, 300 MHz): δ 7.67 (s, 1H), 7.33 (s, 4H), 5.25 (br s, 2H), 4.61(m, 1H), 4.54 (s, 2H), 4.45 (m, 1H), 3.72 (m, 1H), 3.71 (s, 3H), 3.63(m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.9, 154.4, 138.8, 134.1, 128.2,127.3, 127.2, 117.7, 83.1 (d, J_(CF)=165 Hz), 72.9, 72.0, 69.4 (d,J_(CF)=22.5 Hz), 40.7; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₅H₁₆³⁵ClFN₂O₃: 395.1532, found 395.1522.

Example 4 Preparation of4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-phenylpyridazin-3(2H)-onePart A—Preparation of 4,5-dichloro-2-phenylpyridrazin-3(2H)-one

Prepared according to General Method A, using mucochloric acid (0.985 g,5.83 mmol), sodium carbonate (0.309 g, 2.91 mmol), and phenyl hydrazinehydrochloride (0.843 g, 5.83 mmol). Isolated yield—1.31 g; 93.2%. ¹H NMR(CDCl₃, 300 MHz): δ 7.91 (s, 1H), 7.59-7.54 (m, 2H), 7.48-7.39 (m, 3H);¹³C NMR (CDCl₃, 75 MHz): δ 156.1, 140.9, 136.4, 136.1, 135.3, 128.9,128.8, 125.2; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₀H₆ ³⁵Cl₂N₂O:240.9930, found 240.9932.

Part B—Preparation of4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-phenylpyridazin-3(2H)-one

Prepared according to General Method B, using the product of Example 4A(0.070 g, 0.290 mmol), (4-((2-fluoroethoxy)methyl)phenyl)methanol (0.160g, 0.870 mmol), and cesium carbonate (0.283 g, 0.870 mmol) indimethylformamide (2.90 mL) at 80° C. Isolated yield—45 mg; 40%. ¹H NMR(CDCl₃, 300 MHz): δ 7.84 (s, 1H), 7.49-7.30 (m, 9H), 5.31 (s, 2H), 4.59(m, 1H), 4.54 (s, 2H), 4.44 (m, 1H), 3.71 (m, 1H), 3.61 (m, 1H); ¹³C NMR(CDCl₃, 75 MHz): δ 158.3, 154.0, 141.2, 138.9, 134.0, 128.8, 128.3,128.2, 128.0, 127.4, 127.1, 125.3, 81.6 (d, J_(CF)=60 Hz), 73.1, 72.1,69.5 (d, J_(CF)=15 Hz); HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₀H₁₈³⁵ClFN₂O₃: 327.0906, found 327.0901.

Example 5 Preparation of4-chloro-2-cyclohexyl-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of 4,5-dichloro-2-cyclohexylpyridrazin-3(2H)-one

Prepared according to General Method A, using mucochloric acid (0.443 g,2.62 mmol), sodium carbonate (0.138 g, 1.31 mmol), and cyclohexylhydrazine hydrochloride (0.403 g, 2.62 mmol). Isolated yield—0.440 g;67.9%. ¹H NMR (CDCl₃, 600 MHz): δ 7.74 (s, 1H), 4.77 (tt, J=11.6, 3.6Hz, 1H), 1.79 (m, 4H), 1.68-1.56 (m, 3H), 1.44-1.30 (m, 2H), 1.21-1.06(m, 1H); ¹³C NMR (CDCl₃, 150 MHz): δ 156.3, 135.7, 135.1, 133.6, 58.5,31.1, 25.4, 25.2; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₀H₁₂³⁵Cl₂N₂O: 247.0399, found 247.0399.

Part B—Preparation of4-chloro-2-cyclohexyl-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using the product of Example 5A(31 mg, 0.13 mmol), (4-((2-fluoroethoxy)methyl)phenyl)methanol (29 mg,0.16 mmol), and cesium carbonate (0.123 g, 0.380 mmol) indimethylformamide (1.26 mL) at 55° C. Isolated yield—25 mg; 49%.HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₀H₂₄ ³⁵ClN₂O₃: 389.1063, found389.1054.

Example 6 Preparation of2-(tert-butyl)-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

2-(tert-Butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one(0.184 g, 0.50 mmol; e.g., see Purohit, A.; Radeke, H. S.; Azure, M.;Hanson, K.; Benetti, R.; Su, F.; Yalamanchili, P.; Yu, M.; Hayes, M.;Guaraldi, M.; Kagan, M.; Robinson, S.; Casebier, D. Synthesis andBiological Evaluation of Pyridazinone Analogs as Potential CardiacPositron Emission Tomography Tracers J. Med. Chem. 2008, 51, 2954) wassuspended in dry toluene (5.00 mL), successively treated withtributyltin hydride (0.161 g, 0.60 mmol) and2,2′-azobis(2-methylpropionitrile) (0.004 mg, 0.025 mmol), then heatedto reflux and maintained 20 h. After cooling to ambient temperature, allvolatiles were removed in vacuo, and the residue directly purified bychromatography on silica (30×190 mm) using a step gradient from 3:1hexanes/ethyl acetate (400 mL) to 2:1 hexanes/ethyl acetate (500 mL).The main product peak eluting 550-750 mL was collected, pooled andconcentrated in vacuo to a colorless oil (0.101 g, 0.302 mmol; 60.3%).¹H NMR: (600 MHz, DMSO-d₆) δ 7.72 (1H, d, J=2.9 Hz), 7.43 (2H, AB,J_(A)=8.1 Hz), 7.37 (2H, AB, J_(AB)=8.1 Hz), 6.26 (1H, d, J=2.9 Hz),5.11 (s, 2H), 4.63-4.58 (1H, m), 4.54 (2H, s), 4.53-4.49 (1H, m),3.73-3.68 (1H, m), 3.68-3.63 (1H, m), 1.55 (9H, s). ¹³C NMR: (151 MHz,DMSO-d₆) δ 161.5, 158.4, 138.4, 134.4, 130.2, 128.1, 127.6, 105.5, 82.9(d, J_(CF)=166 Hz), 71.6, 69.8, 69.0 (d, J_(CF)=19.0 Hz), 63.6, 27.6.HRMS Calcd. for C₁₈H₂₃FN₂O₃ (M+H): 335.1766; found: 335.1766. TLC: R_(f)0.38 (silica gel, 1:1 hexanes/ethyl acetate, CAM).

Example 7 Preparation of4-bromo-2-(tert-butyl)-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using4,5-dibromo-2-(tert-butyl)pyridazin-3(2H)-one (0.310 g, 1.00 mmol; e.g.,see Taniguchi M.; Ochiai Y.; Hirose M.; Hirata K.; Baba M. (NissanChemical Industries) Benzylthio pyridazinone derivatives, preparationthereof, and insecticidal acaricidal, fungicidal compositions. U.S. Pat.No. 4,877,787, Oct. 31, 1989),(4-((2-fluoroethoxy)methyl)phenyl)methanol (92.1 mg, 0.500 mmol), andcesium carbonate (0.326 g, 1.00 mmol) in dimethylformamide (2.50 mL) at65° C. Isolated yield—0.121 g; 58.5%. ¹H NMR: (300 MHz, CDCl₃) δ 7.62(1H, s), 7.41 (4H, s), 5.32 (2H, s), 4.73-4.64 (1H, m), 4.61 (2H, s),4.57-4.48 (1H, m), 3.85-3.75 (1H, m), 3.75-3.65 (1H, m), 1.63 (9H, s).¹³C NMR: (75 MHz, CDCl₃) δ 159.3, 155.8, 138.8, 134.6, 128.4, 127.4,124.8, 110.5, 83.3 (d, J_(CF)=169 Hz), 73.2, 71.8, 69.7 (d, J_(CF)=19.6Hz), 66.7, 28.1. HRMS Calcd. for C₁₈H₂₂ ⁷⁹BrFN₂O₃ (M+H): 413.0871;found: 413.0876. TLC: R 0.31 (silica gel, 7:3 hexanes/ethyl acetate,CAM).

Example 8 Preparation of4-chloro-2-cyclohexyl-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

To a cooled (0° C.) solution of isopropyl magnesium bromide (0.087 mL, 2M solution in tetrahydrofuran) was added2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-4-pyridazin-3(2H)-one(32 mg, 0.087 mmol) dissolved in tetrahydrofuran (0.783 mL). Thereaction was stirred at 0° C. for 2 h then treated with additionalequivalents of isopropyl magnesium bromide (0.261 mL, 2M solution intetrahydrofuran). After 24 h, the reaction was quenched with water (0.5mL) and diluted with ethyl acetate (20 mL). The organic layer wasseparated, washed with saturated aqueous sodium chloride (3×50 mL),dried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude material was then purified using silica gel chromatography 3:1hexanes/ethyl acetate to afford the desired product as a clear oil (12.0mg, 36.6% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.67 (s, 1H), 7.41 (d,J=7.5 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 5.17 (s, 2H), 4.68 (m, 1H), 4.62(s, 2H), 4.53 (m, 1H), 3.80 (m, 1H), 3.71 (m, 1H), 3.50 (m, 1H), 1.62(s, 9H), 1.27 (d, J=7.1 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 162.3,154.2, 138.3, 135.4, 129.3, 128.1, 127.4, 125.8, 83.1 (d, J_(C)=165 Hz),73.0, 70.8, 69.4 (d, J_(C)=22.5 Hz), 65.0, 28.1, 24.6, 19.5; HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₂₁H₂₉FN₂O₃: 377.2235, found 377.2231.

Example 9 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)-d₂-methyl)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(d₂-hydroxymethyl)benzyl)oxy)pyridazin-3(2H)-one

To a solution of methyl4-(((1-tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate(1.50 g, 4.28 mmol; e.g., see Cesati, R; Cheesman, E. H.; Lazewatsky,J.; Radeke, S.; Castner, J. F.; Mongeau, E.; Zdankiewicz, D. D.;Siegler, R. W.; Devine, M. Methods and apparatus for synthesizingimaging agents, and intermediates thereof PCT Int. Appl. (2011), WO2011/097649, Aug. 8, 2011) in tetrahydrofuran (42.8 mL) at 0° C. wasadded lithium aluminum deuteride (2.14 mL, 2.14 mmol, 1 M solution intetrahydrofuran) dropwise. The resulting mixture was stirred for 2 hthen treated with water (20 mL). The aqueous layer was separated andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated to yield a white solid (1.36 g, 97.8%yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.64 (s, 1H), 7.35 (br s, 4H), 5.24(s, 2H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz, partial): δ 159.0, 153.7,141.5, 134.3, 127.5, 127.3, 125.1, 118.4, 71.7, 64.4, 27.9; HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₇D₂ ³⁵ClN₂O₃: 325.1283, found325.1284.

Part B—Preparation5-((4-(bromo-d₂-methyl)benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

Prepared according to General Method C, using the product of Example 9A(0.882 g, 2.72 mmol) and phosphorous tribromide (1.36 mL, 1.36 mmol, 1 Min dichloromethane). Isolated yield—0.981 g; 93.0%. ¹H NMR (CDCl₃, 300MHz): δ 7.64 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H),5.23 (s, 2H), 1.59 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz, partial): δ 159.0,153.6, 138.3, 135.1, 129.6, 127.5, 125.0, 118.4, 71.4, 66.5, 27.9;HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₆D₂ ⁷⁹Br³⁵ClN₂O₂: 387.0438,found 387.0439.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)-d₂-methyl)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method E, using potassium tert-butoxide(25.3 mg, 0.225 mmol), 2-fluoroethanol (14.5 mg, 0.226 mmol) and theproduct of Example 9B (0.105 g, 0.271 mmol). Isolated yield—7.5 mg;9.8%. ¹H NMR (CDCl₃, 300 MHz): δ 7.74 (s, 1H), 7.33 (s, 4H), 5.24 (s,2H), 4.60 (m, 1H), 4.45 (s, 1H), 3.72 (m, 1H), 3.63 (m, 1H), 1.56 (s,9H); ¹³C NMR (CDCl₃, 75 MHz, partial): δ 159.0, 153.7, 138.6, 134.4,128.3, 127.3, 125.1, 118.4, 83.1 (d, J_(CF)=165 Hz), 71.7, 69.4 (d,J_(CF)=15 Hz), 66.4, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₁₈H₂₀D₂ ³⁵ClFN₂O₃: 371.1501, found 371.1507.

Example 10 Preparation of2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-d₂-methyl)benzyl)oxy)ethyl-4-methylbenzenesulfonate Part A—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-hydroxyethoxy)-d₂-methyl)benzyl) oxy)pyridazin-3(2H)-one

A suspension of potassium tert-butoxide (0.174 g, 1.55 mmol) in ethyleneglycol (0.685 mL) was heated to 60° C. for 20 min then treated with asolution of the product of Example 9B (0.720 g, 1.86 mmol) intetrahydrofuran (21 mL). The resulting mixture was heated to reflux,maintained 16 h then cooled to ambient temperature and treated withwater (15 mL). The aqueous layer was separated then extracted with ethylacetate (3×50 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The crude material was thenpurified using silica gel chromatography (20-50% ethyl acetate inhexanes) to afford the desired product as a yellow oil (0.144 g, 25.2%yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.65 (s, 1H), 7.33 (s, 4H), 5.24 (s,2H), 3.71 (m, 2H), 3.54 (m, 2H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz,partial): δ 159.0, 153.6, 138.6, 134.4, 128.3, 127.2, 125.0, 118.3,71.6, 71.5, 66.4, 61.9, 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₁₈H₂₁D₂ ³⁵ClN₂O₄: 369.1545, found 369.1548.

Part B—Preparation of2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-d₂-methyl)benzyl)oxy)ethyl-4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 10A(78.2 mg, 0.213 mmol), p-toluenesulfonyl chloride (48.6 mg, 0.255 mmol),4-dimethylaminopyridine (31.2 mg, 0.255 mmol), and diisopropylethylamine(0.044 mL, 0.255 mmol). Isolated yield—32.8 mg; 29.4%. ¹H (CDCl₃, 600MHz): δ 7.72 (d, J=8.4 Hz, 2H), 7.65 (s, 1H), 7.31 (d, J=8.3 Hz, 2H),7.26-7.19 (m, 4H), 5.23 (s, 2H), 4.13 (m, 2H), 3.62 (m, 2H), 2.37 (s,3H), 1.51 (s, 9H); ¹³C (CDCl₃, 150 MHz, partial): δ 159.0, 153.6, 144.8,138.3, 134.4, 133.0, 129.8, 128.2, 128.0, 127.2, 125.0, 118.3, 71.6,69.2, 67.7, 66.4, 27.8, 21.6; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₂₅H₂₇D₂ ³⁵ClN₂O₆S: 523.1633, found 523.1629.

Example 11 Preparation of2-(2-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenoxy)ethoxy)ethyl-4-methylbenzenesulfonatePart A—Preparation of 2-(2-(4-(hydroxymethyl)phenoxy)ethoxy)ethanol

A suspension of potassium iodide (1.10 g, 6.58 mmol),methyl-4-hydroxybenzoate (2.00 g, 13.1 mmol), cesium carbonate (8.53 g,26.2 mmol), and 2-(2-chloroethoxy)ethanol (3.60 mL, 34.0 mmol) incyclohexanone (40.0 mL) was heated to reflux and maintained 24 h. Aftercooling to ambient temperature, the solids were removed by filtrationand the resulting filtrate concentrated to an orange oil that wasdirectly used in the subsequent reduction without further purification.

A tetrahydrofuran solution (35.0 mL) of the crude ester was cooled to 0°C. then treated with lithium aluminum hydride (9.12 mL, 9.12 mmol, 1 Mtetrahydrofuran solution). Upon complete addition, the resulting mixturewas warmed to ambient temperature and stirred overnight then treatedwith water (20 mL). The layers were then separated and the aqueous layerextracted with ethyl acetate (2×50 mL). The combined organic layers werethen dried over sodium sulfate, filtered and concentrated to a yellowoil (0.789 g, 28.4% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.21 (m, 2H),6.83 (m, 2H), 4.55 (s, 2H), 4.07 (m, 2H), 3.80 (m, 2H), 3.70 (m, 2H),2.60 (m, 2H).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-(2-hydroxyethoxy)ethoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one⁴(0.375 g, 1.85 mmol) in tetrahydrofuran (15.4 mL) was successivelytreated with the product of Example 11A, (0.327 g, 1.54 mmol),triphenylphosphine (0.609 g, 2.32 mmol), and diethylazodicarboxylate(0.404 g, 2.32 mmol) at ambient temperature. After 1 h, all volatileswere removed in vacuo and the residue directly purified by silica gelchromatography using 4:1 diethyl ether/ethyl acetate to afford thedesired product (20 mg, 3% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.72 (s,1H), 7.31 (m, 2H), 6.96 (m, 2H), 5.25 (s, 2H), 4.16 (m, 2H), 3.88 (m,2H), 3.76 (m, 2H), 3.68 (m, 2H), 1.63 (s, 9H).

Part C—Preparation of2-(2-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl) phenoxy)ethoxy)ethyl-4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example11B, (19.7 mg, 0.0495 mmol), p-toluenesulfonyl chloride (11.3 mg, 0.0594mmol), 4-dimethylaminopyridine (7.26 mg, 0.0594 mmol), anddiisopropylethylamine (0.010 mL, 0.0594 mmol). Isolated yield—5.2 mg;19%. ¹H (CDCl₃, 300 MHz): δ 7.72 (d, J=8.3 Hz, 2H), 7.66 (s, 1H),7.28-7.19 (m, 4H), 6.85 (m, 2H), 5.18 (s, 2H), 4.14 (m, 2H), 3.99 (m,2H), 3.74-3.68 (m, 4H), 2.34 (s, 3H), 1.56 (s, 9H).

Example 12 Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-(2-fluoroethoxy)ethoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 11C (1.90 mg, 0.0034 mmol),tetraethylammonium fluoride (0.85 mg, 0.0046 mmol), andtetraethylammonium bicarbonate (0.88 mg, 0.0046 mmol) in acetonitrile(0.70 mL) was heated to 90° C. and maintained 10 min. After cooling toambient temperature, all volatiles were removed in vacuo and the residuedirectly purified by preparative thin layer chromatography using 4:1hexanes/ethyl acetate to afford the desired product (0.2 mg, 15% yield).API-ES [M+Na] 421.1.

Example 13 Preparation of2-(tert-butyl-4-chloro-5-((4-(2-fluoroethoxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using of2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one³ (68 mg, 0.31 mmol),(4-(2-fluoroethoxy)phenyl)methanol (53 mg, 0.31 mmol, e.g., see Zhou,D.; Chu, W.; Rothfuss, J.; Zeng, C.; Xu, J.; Jones, L.; Welch, M. J.;Mach, R. H. Synthesis, radiolebeling and in vivo evaluation of an18F-labeled isatin analog for imaging caspase-3 activation in apoptosisBioorg. Med. Chem. Lett. 2006, 16, 5041-5045), and cesium carbonate(0.303 g, 0.930 mmol) in dimethylformamide (3.10 mL) at 50° C. Isolatedyield—25 mg; 23%. ¹H NMR (CDCl₃, 300 MHz): δ 7.72 (s, 1H), 7.33 (m, 2H),6.95 (m, 2H), 5.25 (s, 2H), 4.84 (m, 1H), 4.68 (m, 1H), 4.29 (m, 1H),4.16 (m, 1H), 1.57 (s, 9H).

Example 14 Preparation of2-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenoxy)ethyl-4-methylbenzenesulfonatePart A—Preparation of methyl 4-(2-hydroxyethoxy)benzoate

A suspension of methyl 4-hydroxybenzoate (1.52 g, 1.00 mmol),1-bromoethanol (1.05 mL, 1.5 mmol), and cesium carbonate (8.13 g, 2.5mmol) in dimethylformamide (100 mL) was heated to 65° C. and maintainedovernight. After cooling to ambient temperature, the resulting mixturewas diluted with water (250 mL) then extracted with ethyl acetate (3×250mL). The combined organic layers were washed with water and saturatedaqueous sodium chloride then dried over sodium sulfate, filtered andconcentrated to a yellow oil (1.83 g, 93.3% yield). ¹H NMR (CDCl₃, 300MHz): δ 7.92 (m, 2H), 6.86 (m, 2H), 4.45 (s, 3H), 4.08 (m, 2H), 3.92 (m,2H); ¹³C NMR (CDCl₃, 75 MHz): δ 166.8, 162.4, 131.6, 123.1, 114.2, 69.4,61.3, 51.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₀H₁₂O₄: 197.0808,found 197.0811.

Part B—Preparation of(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)methanol

A solution of the product of Example 14A (1.00 g, 5.07 mmol), indimethylformamide (50.0 mL) was successively treated withtert-butyldimethylsilyl chloride (1.14 g, 7.61 mmol) and imidazole(0.518 g, 7.61 mmol) at ambient temperature. After 1 h, the solution wasdiluted with 0.1 N hydrochloric acid (30 mL) then extracted with ethylacetate (3×150 mL). The combined organic layers were washed withsaturated aqueous sodium chloride, dried over sodium sulfate, filtered,and concentrated in vacuo to obtain a crude oil, which was used withoutfurther purification in the subsequent step.

The crude silyl ether (0.965 g, 3.11 mmol) was dissolved intetrahydrofuran (31.1 mL), cooled to 0° C. then treated with lithiumaluminum hydride (1.55 mL, 1.55 mmol, 1 M solution of lithium aluminumhydride in tetrahydrofuran) and warmed to ambient temperature. After 4h, the resulting mixture was treated with water (10 mL) and the layersseparated. The aqueous layer was extracted with ethyl acetate (3×50 mL)and the combined organic layers dried over sodium sulfate, filtered thenconcentrated in vacuo to afford an oil (0.779 g, 54.4% yield). ¹H NMR(DMSO-d₆, 300 MHz): δ 7.14 (m, 2H), 6.80 (m, 2H), 4.96 (t, J=5.7 Hz,1H), 4.35 (d, J=5.6 Hz, 2H), 3.95-3.83 (m, 4H), 0.80 (s, 9H), 0.01 (s,6H).

Part C—Preparation of2-(tert-butyl)-5-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzyl)oxy)-4-chloropyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.465 g, 2.29 mmol) in tetrahydrofuran (27.6 mL) was successivelytreated was added the product of Example 14B (0.779 g, 2.76 mmol),triphenylphosphine (0.905 g, 3.45 mmol), and diisopropylazodicarboxylate(0.686 mL, 3.45 mmol) at ambient temperature. After 20 min, theresulting mixture was treated with water (5 mL), the aqueous layerseparated then extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified using silicagel chromatography (20-50% ethyl acetate in hexanes) to afford thedesired product as a clear oil (0.359 g, 33.6% yield). ¹H NMR (CDCl₃,300 MHz): δ 7.63 (s, 1H), 7.23 (m, 2H), 6.86 (m, 2H), 5.15 (s, 2H), 4.01(m, 2H), 3.87 (m, 2H), 1.53 (s, 9H), 0.82 (s, 9H), 0.01 (s, 6H); ¹³C NMR(CDCl₃, 75 MHz, partial): δ 159.1, 153.7, 129.0, 127.4, 125.3, 118.4,115.0, 71.8, 69.9, 66.4, 61.4, 27.9, 26.6, −3.6; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₂₃H₃₅ ³⁵ClN₂O₄Si:467.2127, found 467.2128.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-hydroxyethoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 14C (0.240 g, 0.513 mmol) intetrahydrofuran (5.13 mL) was treated with tetrabutylammonium fluoride(1.03 mL, 1.03 mmol, 1 M solution in tetrahydrofuran) dropwise atambient temperature. After 40 min, the resulting mixture was dilutedwith water (5 mL) the aqueous layer was separated then extracted withethyl acetate (3×15 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated to afford an off white solid(0.157 g, 86.7% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.62 (s, 1H), 7.27(m, 2H), 7.89 (m, 2H), 5.18 (s, 2H), 4.03 (m, 2H), 3.90 (m, 2H), 1.57(s, 9H); ¹³C NMR (CDCl₃, 75 MHz, partial): δ 159.1, 153.8, 129.0, 127.4,125.3, 118.4, 115.0, 71.7, 69.3, 66.4, 61.4, 27.9; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₇H₂₁ ³⁵ClN₂O₄: 375.1082, found 375.1079.

Part E—Preparation of2-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenoxy)ethyl-4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 14D(0.157 g, 0.446 mmol), p-toluenesulfonyl chloride (0.102 g, 0.536 mmol),4-dimethylaminopyridine (81.9 mg, 0.67 mmol), and triethylamine (0.075mL, 0.536 mmol). Isolated yield—0.120 g; 53.1%. ¹H (CDCl₃, 600 MHz): δ7.74 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.28-7.19 (m, 4H), 6.75 (m, 2H),5.16 (s, 2H), 4.30 (m, 2H), 4.09 (m, 2H), 2.38 (s, 3H), 1.56 (s, 9H); ³CNMR (CDCl₃, 150 MHz): δ 159.0, 158.5, 153.7, 145.0, 132.9, 129.9, 128.9,128.0, 127.7, 125.2, 118.4, 115.0, 71.7, 67.9, 66.4, 65.6, 27.9, 21.6;HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₄H₂₇ ³⁵ClN₂O₆S: 507.1351,found 507.1365.

Example 15 Preparation of2-(1-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenyl)ethoxy)ethyl 4-methylbenzenesulfonate Part A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-methyl-1,3-dioxolan-2-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4,5-dichloro-2-hydropyridazin-3-one (1.66g, 7.50 mmol) and (4-(2-methyl-1,3-dioxolan-2-yl)phenyl)methanol (0.971g, 5.00 mmol; e.g., see Takebayashi, S.; Dabral, N.; Miskolzie, M.;Bergens, S. H. J. Am. Chem. Soc., 2011, 133, 25, 9666-9669) in drydimethylformamide (50.0 mL) was treated with cesium carbonate (3.26 g,10.0 mmol) in one portion at ambient temperature. The resultingsuspension was then immersed in a pre-heated oil bath, and maintained at65° C., with vigorous stirring, 4 h. After cooling to ambienttemperature, the suspension was maintained an additional 12 h, thenpartitioned between ethyl acetate and water (50 mL each), with transferto a separatory funnel. The layers were then separated, and the aqueouslayer washed with ethyl acetate (2×50 mL). The combined ethyl acetatewashes were further washed with saturated aqueous sodium chloride (5×50mL), then dried over magnesium sulfate, filtered and concentrated invacuo to a yellow solid. The crude material was then purified bychromatography on silica (40×220 mm) using 7:3 pentane/ethyl acetate.The main product peak eluting 400-700 mL was collected, pooled andconcentrated in vacuo to a white solid. The purified material was thenrecrystallized from hot ethyl acetate/pentane to afford colorlessneedles (1.33 g, 3.51 mmol; 70.1%). ¹H NMR: (300 MHz, DMSO-d₆) δ 8.27(1H, s), 7.52-7.36 (4H, m), 5.44 (2H, s), 4.07-3.93 (2H, m), 3.76-3.60(2H, m), 1.57 (9H, s), 1.55 (3H, s). ¹³C NMR: (75 MHz, DMSO-d₆) 157.8,153.9, 143.6, 134.9, 127.7, 126.2, 125.4, 115.5, 107.9, 71.2, 65.4,64.1, 27.5, 27.2. HRMS Calcd. for C₁₉H₂₃ ³⁵ClN₂O₄ (M+H): 379.1419;found: 379.1416. TLC: R_(f) 0.39 (silica gel, 7:3 pentane/ethyl acetate,uv).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(1-(2-hydroxyethoxy)ethyl)benzyl)oxy)pyridazin-3(2H)-one

A 25 mL flame-dried round bottom flask was charged with zirconiumchloride (0.233 g, 1.00 mmol) and dry tetrahydrofuran (3.00 mL) atambient temperature. The resulting solution was then treated with sodiumborohydride (75.7 mg, 2.00 mmol), in one portion, followed by theproduct of Example 15A (1.00 mmol; 2.00 mL of a 0.5 M solution intetrahydrofuran), dropwise over 3 min at ambient temperature. After 1.5h, excess sodium borohydride was then consumed by the dropwise additionof water and the resulting solution partitioned between ethyl acetateand water (25 mL each) with transfer to a separatory funnel. The layerswere then separated, and the aqueous layer washed with ethyl acetate(2×25 mL).

The combined ethyl acetate washes were then dried over magnesiumsulfate, filtered and concentrated in vacuo. The crude material thusobtained was then purified by chromatography on silica (30×170 mm) using1:1 pentane/ethyl acetate. The main product peak eluting 250-460 mL wascollected, pooled and concentrated in vacuo to a colorless oil (0.289 g,0.758 mmol; 75.8%). ¹H NMR: (300 MHz, CDCl₃) δ 7.74 (1H, s), 7.45-7.29(4H, m), 5.29 (2H, s), 4.47 (1H, q, J=6.5 Hz), 3.79-3.63 (2H, m),3.52-3.35 (2H, m), 1.63 (9H, s), 1.46 (3H, d, J=6.5 Hz). ¹³C NMR: (75MHz, CDCl₃) δ 159.0, 153.7, 144.3, 134.1, 127.4, 126.7, 125.1, 118.3,78.1, 71.7, 69.8, 66.4, 62.0, 27.9, 23.9. HRMS Calcd. for C₁₉H₂₅³⁵ClN₂O₄(M+H): 381.1576; found: 381.1574.

Part C—Preparation of2-(1-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenyl)ethoxy)ethyl4-methylbenzenesulfonate

A solution of the product of Example 15B (95.2 mg, 0.250 mmol) in drypyridine (0.50 mL) was cooled to 0° C. then treated withp-toluenesulfonyl chloride (95.3 mg, 0.50 mmol) in one portion. After0.25 h, the resulting solution was then warmed to ambient temperatureand maintained 3.25 h, when additional p-toluenesulfonyl chloride (95.3mg, 0.50 mmol) was added. After 0.75 h, the resulting solution wasdiluted with ethyl acetate (150 mL) and water (50 mL), with transfer toa separatory funnel. The layers were then separated and the ethylacetate layer successively washed with 0.1 M hydrochloric acid andsaturated aqueous sodium bicarbonate (3×50 mL each), then dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial thus obtained was then purified by chromatography on silica(30×175 mm) using 3:2 pentane/ethyl acetate. The main product peakeluting 150-250 mL was collected, pooled and concentrated in vacuo to acolorless oil (62.1 mg, 0.116 mmol; 46.4%). ¹H NMR: (300 MHz, DMSO-d₆) δ8.28 (1H, s), 7.82-7.71 (2H, AA′BB′, J_(AB)=8.3 Hz, J_(AA′)=2.0 Hz),7.45 (2H, AB, d, J_(AB)=8.6 Hz), 7.42 (2H, AB, J_(AB)=8.1 Hz), 7.28 (2H,AB, J_(AB)=8.1 Hz), 5.44 (2H, s), 4.42 (1H, q, J=6.4 Hz), 4.11 (2H,ABdd, J_(AB)=11.2 Hz, J_(dd)=5.7, 3.0 Hz), 3.40 (2H, ABdd, J_(AB)=11.9Hz, J_(dd)=5.6, 3.0 Hz), 2.41 (3H, s), 1.57 (9H, s), 1.27 (3H, d, J=6.4Hz). ¹³C NMR: (75 MHz, DMSO-d₆) δ 157.8, 153.9, 144.8, 143.6, 134.5,132.5, 130.1, 127.9, 127.6, 126.2, 126.2, 115.5, 76.7, 71.3, 70.1, 65.5,65.4, 27.5, 23.4, 21.0. HRMS Calcd. for C₂₆H₃₁ ³⁵ClN₂O₆S (M+H):535.1644; found: 535.1657. TLC: R_(f) 0.58 (silica gel, 1:1pentane/ethyl acetate, uv).

Example 16 Preparation of2-(tert-butyl)-4-chloro-5-((4-(1-(2-fluoroethoxy)ethyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 15C (79.7 mg, 0.150 mmol) and4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (113 mg,0.200 mmol) in dry acetonitrile (1.50 mL) was treated with potassiumfluoride (17.4 mg, 0.300 mmol) in one portion at ambient temperature.The resulting suspension was then immersed in a pre-heated oil bath, andmaintained at 90° C. for 0.25 h. After cooling to ambient temperature,all volatiles were removed in vacuo, and the residue directly purifiedby chromatography on silica (30×160 mm) using 1:1 pentane/diethyl ether.The main product peak eluting 140-220 mL was collected, pooled andconcentrated in vacuo to a colorless oil (42.6 mg, 0.111 mmol; 74.2%).¹H NMR: (300 MHz, CDCl₃) δ 7.74 (1H, s), 7.45-7.30 (4H, m), 5.29 (2H,s), 4.53 (2H, ddd, J=47.7, 4.7, 3.7 Hz), 4.51 (1H, q, J=6.5 Hz),3.69-3.53 (1H, m), 3.59-3.44 (1H, m), 1.63 (9H, s), 1.47 (3H, d, J=6.5Hz). ¹³C NMR: (75 MHz, CDCl₃) δ 159.0, 153.7, 144.2, 134.1, 127.4,126.7, 125.1, 118.3, 83.1 (d, J_(CF)=169 Hz), 78.1, 71.7, 67.7 (d,J_(CF)=19.8 Hz), 66.4, 27.8, 24.0. ¹⁹F NMR (282 MHz, CDCl₃) 5-223.2 (tt,J=47.8, 29.6 Hz). HRMS Calcd. for C₁₉H₂₄ ³⁵ClFN₂O₃ (M+H): 383.1532;found: 383.1531. TLC: R_(f) 0.40 (silica gel, 1:1 pentane/diethyl ether,uv).

Example 17 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoropropoxy)ethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

A suspension of potassium tert-butoxide (0.174 g, 1.55 mmol),3-fluoropropyl p-toluenesulfonate (0.152 g, 0.654 mmol), and2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)-4-pyridazin-3(2H)-one (0.200 g, 0.59 mmol) intetrahydrofuran (5.90 mL) was heated to reflux and maintained overnight.After cooling to ambient temperature, the resulting mixture was treatedwith water (15 mL), the aqueous layer separated then extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo. The crude materialwas then purified by preparative thin layer chromatography on silicausing 4:1 hexanes/ethyl acetate to afford the desired product as ayellow oil (0.8 mg, 1% yield). API-ES (m/z): [M+H] 427.2.

Example 18 Preparation of2-(tert-butyl)-4-chloro-5-((4-(((2-fluoroethyl)amino)methyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of5-((4-(bromomethyl)benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one³(0.200 g, 0.521 mmol) in dimethylformamide (5.20 mL) was successivelytreated with 2-fluoroethylamine hydrochloride (62.2 mg, 0.625 mmol) anddiisopropylethylamine (0.136 mL, 0.782 mmol) at ambient temperature.After 2 d, the resulting mixture was diluted with water (50 mL), theaqueous layer separated then extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was then purified using silicagel chromatography (50-80% ethyl acetate in hexanes) to afford thedesired product as a clear oil (17.2 mg, 9.0% yield). ¹H NMR (CDCl₃, 600MHz): δ 7.64 (s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H),5.22 (s, 2H), 4.65 (m, 1H), 4.50 (m, 1H), 3.90 (s, 2H), 2.97 (m, 1H),2.88 (m, 1H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 150 MHz): δ 158.0, 152.7,138.1, 133.1, 128.0, 126.9, 126.4, 117.3, 81.8 (d, J_(CF)=165 Hz), 70.7,65.4, 51.8, 47.4 (d, J_(CF)=22.5 Hz), 26.9; HRMS-TOF (m/z): [M+H]⁺ HRMS:Calcd. for C₁₈H₂₃ ³⁵ClFN₃O₂: 368.1536, found 368.1533.

Example 19 Preparation of2-(tert-butyl)-4-chloro-5-((4-(fluoromethyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of5-((4-(bromomethyl)benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one³(0.110 g, 0.285 mmol) in dry acetonitrile (2.85 mL) was treated withsilver fluoride (72.4 mg, 0.570 mmol) in one portion at ambienttemperature. After 0.25 h, the resulting suspension was then immersed ina pre-heated oil bath, and maintained at 65° C. for 0.75 h, whenadditional silver fluoride (72.4 mg, 0.570 mmol) was added. After 1 h,the resulting suspension was cooled to ambient temperature, allvolatiles removed in vacuo, and the residue directly purified bychromatography on silica (25×185 mm) using 4:1 hexanes/ethyl acetate.The main product peak eluting 280-420 mL was collected, pooled andconcentrated in vacuo to a white solid (64.6 mg, 0.199 mmol; 69.8%). ¹HNMR: (300 MHz, DMSO-d₆) δ 8.25 (1H, s), 7.56-7.42 (4H, m), 5.48 (2H, d,J=1.4 Hz), 5.43 (2H, d, J=47.7 Hz), 1.57 (9H, s). ¹³C NMR: (75 MHz,DMSO-d₆) δ 157.8, 153.8, 136.4 (d, J_(CF)=16.7 Hz), 135.9 (d, J_(CF)=3.1Hz), 128.1 (d, J_(CF)=5.7 Hz), 127.9 (d, J_(CF)=1.4 Hz), 126.1, 115.6,83.8 (d, J_(CF)=162 Hz), 71.1, 65.4, 27.4. ¹⁹F NMR: (282 MHz, DMSO-d₆)5-205.4 (t, J=47.7 Hz). HRMS Calcd. for C₁₆H₁₈ ³⁵ClFN₂O₂ (M+H):325.1114; found: 325.1117. TLC: R_(f) 0.24 (silica gel, 4:1hexanes/ethyl acetate, uv).

Example 20 Preparation of2-(tert-butyl)-4-chloro-5-((4′-fluoro-[1,1′-biphenyl]-4-yl)methoxy)pyridazin-3(2H)-onePart A—Preparation of (4′-fluoro-[1,1′-biphenyl]-4-yl)methanol

A solution of 4-(4-fluorophenyl)benzoic acid (0.500 g, 2.31 mmol) intetrahydrofuran (23.1 mL) was cooled to 0° C., treated with lithiumaluminum hydride (1.15 mL, 1.15 mmol, 1 M solution in tetrahydrofuran)then warmed to ambient temperature and stirred overnight. The resultingmixture was then treated with water (20 mL), the aqueous layer separatedthen extracted with ethyl acetate (3×100 mL). The combined organiclayers were washed with saturated aqueous sodium chloride, dried oversodium sulfate, filtered and concentrated to a white solid (0.290 g,62.1% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.48-7.44 (m, 2H), 7.46 (d,J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.04 (m, 2H), 4.67 (s, 2H); ¹³CNMR (CDCl₃, 75 MHz): δ 161.5 (d, J_(CF)=240 Hz), 138.9, 138.7, 136.0 (d,J_(CF)=7.5 Hz), 127.7 (d, J_(CF)=7.5 Hz), 126.5, 126.2, 114.6 (d,J_(C)=22.5 Hz), 64.0; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for Cl₃H₁₁FO:203.0867, found 203.0868.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4′-fluoro-[1,1′-biphenyl]-4-yl)methoxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.288 g, 1.30 mmol),the product of Example 20A, (0.290 g, 1.43 mmol), and cesium carbonate(0.680 g, 2.09 mmol) in dimethylformamide (13.0 mL) at 60° C. Isolatedyield—0.144 g; 28.6%. ¹H NMR (CDCl₃, 300 MHz): δ 7.68 (s, 1H), 7.53 (d,J=8.5 Hz, 2H), 7.53-7.45 (m, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.06 (m, 2H),5.28 (s, 2H), 1.54 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 162.7 (d,J_(CF)=247.5 Hz), 159.0, 153.7, 140.8, 136.5 (d, J_(CF)=7.5 Hz), 133.9,128.7 (d, J_(CF)=7.5 Hz), 127.7, 127.6, 125.1, 118.4, 115.8 (d,J_(CF)=22.5 Hz), 71.6, 66.4, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd.for C₂₁H₂₀ ³⁵ClFN₂O₂: 387.1270, found 387.1268.

Example 21 Preparation of2-(tert-butyl)-4-chloro-5-((5-((2-fluoroethoxy)methyl)pyridin-2-yl)methoxy)pyridazin-3(2H)-onePart A—Preparation of methyl6-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-ol)oxy)methyl)nicotinate

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (0.917 g, 4.54mmol), methyl 6-(bromomethyl)nicotinate (0.994 g, 4.32 mmol), and cesiumcarbonate (2.25 g, 6.91 mmol) in dimethylformamide (21.0 mL) at 60° C.Isolated yield—0.666 g; 41.7%. ¹H NMR (CDCl₃, 300 MHz): δ 9.22 (d, J=1.3Hz, 1H), 8.41 (dd, J=8.1, 2.1 Hz, 1H), 7.79 (s, 1H), 7.69 (d, J=8.2 Hz,1H), 5.48 (s, 2H), 3.99 (s, 3H), 1.66 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz):δ 165.2, 159.1, 158.9, 153.3, 150.4, 138.6, 125.9, 124.7, 120.8, 118.5,70.7, 66.7, 52.6, 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₈³⁵ClN₃O₄: 352.1059, found 352.1059.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((5-(hydroxymethyl)pyridin-2-yl)methoxy)pyridazin-3(2H)-one

A solution of the product of Example 21A (0.333 g, 0.945 mmol) intetrahydrofuran (9.45 mL) was cooled to 0° C., treated with lithiumaluminum hydride (0.472 mL, 0.5 mmol, 1M solution in tetrahydrofuran)then warmed to ambient temperature. After 4 h, the resulting mixture wastreated with water (10 mL), the aqueous layer separated then extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith saturated aqueous sodium chloride, dried over sodium sulfate,filtered and concentrated to a yellow oil (0.290 g, 94.8% yield). ¹H NMR(DMSO-d₆, 600 MHz): δ 8.59 (d, 1H, J=1.4 Hz), 8.32 (s, 1H), 7.87 (dd,J=7.9, 2.2 Hz, 1H), 7.57 (m, 1H), 5.58 (s, 2H), 5.39 (t, J=5.74 Hz, 1H),4.61 (d, J=5.6 Hz, 2H), 1.64 (s, 9H); ¹³C NMR (DMSO-d₆, 150 MHz): δ157.8, 153.9, 153.4, 147.8, 137.4, 135.5, 126.3, 121.6, 115.5, 71.8,64.8, 50.7, 20.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₅H₁₈³⁵ClN₃O₃: 324.1109, found 324.111.

Part C—Preparation of 5-((5-(bromomethyl) pyridin-2-yl)methoxy)-2-(tert-butyl)-4-chloro pyridazin-3(2H)-one

Prepared according to General Method C, using product of Example 21B(0.289 g, 0.891 mmol) and phosphorous tribromide (0.446 mL, 0.446 mmol,1 M in dichloromethane). Isolated yield—0.212 g; 61.5%. ¹H NMR (DMSO-d₆,300 MHz): δ 8.73 (d, J=1.4 Hz, 1H), 8.31 (s, 1H), 8.03 (dd, J=8.1, 2.3Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 5.60 (s, 2H), 4.83 (s, 2H), 1.64 (s,9H); ¹³C NMR (DMSO-d₆, 75 MHz): δ 157.8, 154.8, 153.8, 149.6, 138.0,133.8, 126.3, 121.8, 115.6, 71.8, 66.4, 30.4, 27.5. HRMS-TOF (m/z):[M+H] HRMS: Calcd. for C₅H₁₇ ⁷⁹Br³⁵ClN₃O₂: 386.0265, found 386.0267.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((5-((2-fluoroethoxy)methyl)pyridin-2-yl)methoxy)pyridazin-3(2H)-one

Prepared according to General Method A, using potassium tert-butoxide(25.9 mg, 0.231 mmol), 2-fluoroethanol (14.8 mg, 0.231 mmol) and theproduct of Example 21C (0.100 g, 0.260 mmol). Isolated yield—23.8 mg;27.9%. ¹H NMR (CDCl₃, 300 MHz): δ 8.51 (d, J=1.5 Hz, 1H), 7.73 (s, 1H),7.72 (dd, J=7.3, 2.17 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 5.34 (s, 2H),4.47 (m, 1H), 4.45 (s, 2H), 4.46 (m, 1H), 3.77 (m, 1H), 3.67 (m, 1H),1.48 (s, 9H); HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₇H₂₁ ³⁵ClFN₃O₃:370.1328, found 370.1328.

Example 22 Preparation of5-((3-bromo-4-((2-fluoroethoxy)methyl)benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-onePart A—Preparation of methyl2-bromo-4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (0.750 g, 3.70mmol), methyl 2-bromo-4-bromomethyl benzoate (1.09 g, 3.52 mmol), andcesium carbonate (1.37 g, 4.22 mmol) in dimethylformamide (35.0 mL) at70° C. Isolated yield—0.695 g; 46.0%. ¹H NMR (CDCl₃, 300 MHz): δ 7.84(m, 1H), 7.73 (m, 1H), 7.69 (s, 1H), 7.44 (m, 1H), 5.32 (s, 2H), 3.93(s, 3H), 1.64 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 165.2, 158.9, 153.3,139.9, 132.4, 132.3, 131.9, 125.4, 124.7, 122.3, 118.7, 70.2, 66.6,52.6, 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₇H₁₈ ⁷⁹Br³⁵ClN₂O₄:429.0211, found 429.0209.

Part B—Preparation of 5-((3-bromo-4-(hydroxymethyl) benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

A solution of the product of Example 22A (0.300 g, 0.697 mmol), intetrahydrofuran (2.50 mL) was cooled −20° C., treated withdiisobutylaluminum hydride (1.57 mL, 1.57 mmol, 1 M solution indichloromethane) the warmed to ambient temperature and stirredovernight. The resulting mixture was treated with water (10 mL), theaqueous layer separated then extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was then purified by silicagel chromatography (0-50% ethyl acetate in hexanes) to afford thedesired product as a yellow oil (0.109 g, 38.9% yield). ¹H NMR (DMSO-d₆,300 MHz): δ 8.59 (d, J=1.4 Hz, 1H), 8.32 (s, 1H), 7.87 (dd, J=7.9, 2.2Hz, 1H), 7.57 (m, 1H), 5.58 (s, 2H), 5.39 (t, J=5.7 Hz, 1H), 4.61 (d,J=5.6 Hz, 2H), 1.64 (s, 9H); ¹³C NMR (DMSO-d₆, 75 MHz): δ 159.0, 153.4,140.4, 136.0, 131.0, 129.2, 126.1, 124.9, 122.8, 118.5, 70.7, 66.6,64.7, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₈ ⁷⁹Br³⁵ClN₂O₃:401.0262, found 401.0266.

Part C—Preparation of5-((3-bromo-4-(bromomethyl)benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

Prepared according to General Method C, using the product of Example 22B(0.109 g, 0.270 mmol) and phosphorous tribromide (0.135 mL, 0.135 mmol,1 M in dichloromethane). Isolated yield—87.1 mg; 69.4%. ¹H NMR (CDCl₃,300 MHz): δ 7.69 (s, 1H), 7.64 (d, J=1.4 Hz, 1H), 7.51 (d, J=7.9 Hz,1H), 7.36 (dd, J=7.9, 1.7 Hz, 1H), 5.27 (s, 2H), 4.60 (s, 2H), 1.64 (s,9H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.9, 153.3, 137.6, 137.2, 131.7,131.6, 126.4, 124.9, 124.8 118.6, 70.4, 66.6, 32.6, 27.9; HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₇ ⁷⁹Br₂ ³⁵ClN₂O₂: 464.9397, found464.9400.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((5-((2-fluoroethoxy)methyl)pyridin-2-yl)methoxy)pyridazin-3(2H)-one

Prepared according to General Method E, using potassium tert-butoxide(9.5 mg, 0.084 mmol), 2-fluoroethanol (5.4 mg, 0.084 mmol) and theproduct of Example 22C (43.5 mg, 0.0940 mmol). Isolated yield—3.0 mg;8.0%. ¹H NMR (CDCl₃, 300 MHz): δ 7.69 (s, 1H), 7.61 (d, 1H, J=1.4 Hz),7.57 (d, J=8.0 Hz, 1H), 7.38 (dd, J=6.3, 1.6 Hz, 1H), 5.27 (s, 2H), 4.72(m, 1H), 4.66 (s, 2H), 4.56 (m, 1H), 3.89 (m, 1H), 3.79 (m, 1H), 1.64(s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.0, 153.4, 138.0, 136.0, 131.0,129.4, 126.1, 124.9, 122.9, 118.6, 83.0 (d, J_(CF)=165 Hz), 72.3, 70.7,70.1 (d, J_(CF)=15 Hz), 66.5, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd.for C₁₈H₂₁ ⁷⁹Br³⁵ClFN₂O₃: 447.0481, found 447.0471.

Example 23 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)-2,5-dimethylbenzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(chloromethyl)-2,5-dimethylbenzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (0.500 g, 2.47mmol), 2,5-bis(chloromethyl)-p-xylene (1.00 g, 5.00 mmol), and cesiumcarbonate (2.60 g, 8.00 mmol) in dimethylformamide (25.0 mL) at ambienttemperature. Isolated yield—0.410 g; 44.9%. ¹H NMR (CDCl₃, 300 MHz): δ7.68 (s, 1H), 7.13 (m, 2H), 5.17 (s, 2H), 4.51 (s, 2H), 2.34 (s, 3H),2.28 (s, 3H), 1.58 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.0, 153.7,136.2, 135.1, 134.5, 133.3, 132.2, 130.7, 125.0, 118.3, 70.3, 66.4,44.2, 27.9, 18.4, 18.3; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₈H₂₂³⁵Cl₂N₂O₂: 369.1131, found 369.1134.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)-2,5-dimethylbenzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method E, using potassium tert-butoxide(38.0 mg, 0.339 mmol), 2-fluoroethanol (14.5 mg, 0.226 mmol) and theproduct of Example 23A (0.100 g, 0.271 mmol). Isolated yield—18.3 mg;20.4%. ¹H NMR (CDCl₃, 300 MHz): δ 7.69 (s, 1H), 7.61 (d, J=14.9 Hz, 1H),7.57 (d, J=12.6 Hz, 1H), 5.18 (s, 2H), 4.49 (m, 1H), 4.46 (s, 2H), 4.44(m, 1H), 3.73 (m, 1H), 3.64 (m, 1H), 2.28 (s, 3H), 2.25 (3H, s), 1.53(s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.1, 152.8, 135.6, 133.5, 133.1,131.2, 130.1, 129.5, 124.1, 117.2, 82.1 (d, J_(CF)=165 Hz), 70.4, 69.5,68.6 (d, J_(CF)=22.5 Hz), 65.4, 26.9, 17.4, 17.3; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₂₀H₂₆ ³⁵ClFN₂O₃: 397.1689, found 397.1687.

Example 24 Preparation of2-(tert-butyl)-4-chloro-5-((4-(3-fluoropropoxy)-3-methoxybenzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (4-(3-fluoropropoxy)-3-methoxphenyl)methanol

Prepared according to General Method F, using4-hydroxy-3-methoxybenzaldehyde (0.688 g, 4.52 mmol), 3-fluoropropylp-toluenesulfonate (1.00 g, 4.30 mmol), and cesium carbonate (2.24 mg,6.89 mmol) in dimethylformamide (43.0 mL) at 60° C. Isolated yield—0.517g; 56.1%. ¹H NMR (CDCl₃, 300 MHz): δ 9.78 (s, 1H), 7.37 (dd, J=8.1, 1.9Hz, 1H), 7.35 (m, 1H), 7.63 (d, J=8.1 Hz, 1H), 4.68 (t, J=5.7 Hz, 1H),4.53 (t, J=5.7 Hz, 1H), 4.18 (t, J=6.3 Hz, 2H), 3.12 (s, 3H), 2.24 (m,1H), 2.15 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 190.8, 153.8, 150.0,130.3, 126.7, 111.7, 109.5, 80.5 (d, J_(CF)=165 Hz), 64.8 (d, J_(CF)=7.5Hz), 56.0, 30.2 (d, J_(CF)=22.5 Hz).

A solution of the crude 4-(3-fluoropropoxy)-3-methoxybenzaldehyde (0.839g, 3.90 mmol) in ethanol (39.0 mL) was treated sodium borohydride (0.112g, 2.90 mmol) in one portion at ambient temperature. The resultingmixture was stirred overnight, then treated with water (50 mL) andconcentrated in vacuo to remove the ethanol. The resulting aqueoussolution was extracted with ethyl acetate (3×150 mL), and the combinedorganic layers dried over sodium sulfate, filtered and concentrated toafford the desired product (0.807 g, 96.6% yield). ¹H NMR (CDCl₃, 600MHz): δ 6.87 (br s, 1H), 6.81 (br s, 2H), 4.68 (m, 1H), 4.56 (s, 2H),4.52 (m, 1H), 4.08 (t, J=6.3 Hz, 2H), 3.81 (s, 3H), 2.19 (m, 1H), 2.11(m, 1H); ¹³C NMR (CDCl₃, 150 MHz): δ 149.7, 147.8, 121.5, 119.5, 113.4,111.8, 81.9 (d, J_(CF)=157.5 Hz), 65.3, 65.0 (d, J_(CF)=7.5 Hz), 56.0,30.5 (d, J_(CF)=22.5 Hz); HRMS-TOF (m/z): [M+Na]⁺ HRMS: Calcd. forC₁₁H₁₅FO₃: 237.0897, found 237.0898.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(3-fluoropropoxy)-3-methoxybenzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.200 g, 0.990 mmol) in tetrahydrofuran (8.24 mL) was successivelytreated with the product of Example 24A (0.254 g, 1.19 mmol),triphenylphosphine (0.388 g, 1.48 mmol), and diisopropylazodicarboxylate(0.291 mL, 1.48 mmol) at ambient temperature. The resulting mixture wasstirred overnight then concentrated in vacuo to a yellow oil. The crudematerial was then purified by preparative thin layer chromatography onsilica using 98:2 hexanes/diethyl ether to afford the desired product(12.6 mg, 3.2% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.65 (s, 1H), 6.86 (m,3H), 5.18 (s, 2H), 4.68 (t, J=5.7 Hz, 1H), 4.52 (t, J=5.7 Hz, 1H), 4.09(t, J=6.3 Hz, 2H), 3.08 (s, 3H), 2.24-2.07 (m, 2H), 1.56 (s, 9H); ¹³CNMR (CDCl₃, 75 MHz, partial): δ 159.0, 153.8, 150.0, 148.7, 127.8,125.3, 120.0, 113.2, 110.9, 80.7 (d, J_(CF)=165 Hz), 72.0, 66.4, 64.9(d, J_(CF)=7.5 Hz), 56.0, 30.4 (d, J_(CF)=22.5 Hz), 27.9; HRMS-TOF(m/z): [M+H]⁺ Calcd. for C₁₉H₂₄ ³⁵ClFN₂O₄: 399.1481, found 399.1484.

Example 25 Preparation of2-(tert-butyl)-4-chloro-5-((3-chloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (3-chloro-4-(3-fluoropropoxy)phenyl)methanol

Prepared according to General Method F, using3-chloro-4-hydroxybenzaldehyde (0.300 g, 1.92 mmol), 3-fluoropropylp-toluenesulfonate (424 g, 1.83 mmol), and cesium carbonate (0.951 g,2.93 mmol) in dimethylformamide (19.0 mL) at 65° C. Isolated yield—0.262g; 66.1%. ¹H NMR (CDCl₃, 300 MHz): δ 9.89 (s, 1H), 7.93 (d, J=2.1 Hz,1H), 7.78 (dd, J=8.5, 2.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.80 (t,J=5.7 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 4.28 (t, J=6.0 Hz, 2H), 2.33 (m,1H), 2.22 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 189.6, 159.1, 131.3,130.4, 130.4, 124.0, 112.6, 80.2 (d, J_(CF)=165 Hz), 64.9 (d, J_(CF)=7.5Hz), 30.2 (d, J_(CF)=22.5 Hz).

A solution of the crude 3-chloro-4-(3-fluoropropoxy)benzaldehyde (0.262g, 1.21 mmol) in ethanol (8.95 mL) was treated with sodium borohydride(25.4 mg, 0.671 mmol) in one portion at ambient temperature. Theresulting mixture was stirred overnight, then treated with water (10 mL)and concentrated in vacuo to remove the ethanol. The resulting aqueoussolution was extracted with ethyl acetate (3×50 mL), and the combinedorganic layers dried over sodium sulfate, filtered and concentrated toafford the desired product as a white solid (0.242 g, 91.5% yield). ¹HNMR (CDCl₃, 300 MHz): δ 7.32 (d, J=2.1 Hz, 1H), 7.13 (dd, J=8.4, 2.2 Hz,1H), 6.86 (d, J=8.4 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.57 (t, J=5.6 Hz,1H), 4.54 (s, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.19 (m, 1H), 2.11 (m, 1H);¹³C NMR (CDCl₃, 75 MHz): δ 153.7, 134.4, 129.2, 126.5, 123.1, 113.5,80.6 (d, J_(CF)=165 Hz), 64.8 (d, J_(CF)=7.5 Hz), 64.4, 30.4 (d,J_(CF)=22.5 Hz); HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₀H₁₂ ³⁵ClFO₂:217.0437, found 217.0442.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((3-chloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.186 g, 0.920 mmol) in THF (7.60 mL) was successively treated with theproduct of Example 25A (0.242 g, 1.10 mmol), triphenylphosphine (0.362g, 1.38 mmol), and diisopropylazodicarboxylate (0.362 g, 1.38 mmol) atambient temperature. The resulting mixture was stirred overnight thenconcentrated in vacuo to a yellow oil. The crude material was thenpurified by silica gel chromatography using 4:1 dichloromethane/methanolto afford the desired product as a white solid (53.8 mg, 14.5% yield).¹H NMR (CDCl₃, 300 MHz): δ 7.65 (s, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.20(dd, J=2.3, 4.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.14 (s, 2H), 4.70 (t,J=5.8 Hz, 1H), 4.54 (t, J=5.8 Hz, 1H), 4.10 (t, J=6.0 Hz, 2H), 2.16 (m,1H), 2.11 (m, 1H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.0,154.6, 153.5, 129.4, 128.1, 127.0, 125.1, 123.45, 118.4, 113.5, 80.4 (d,J_(CF)=165 Hz), 71.0, 66.4, 64.7 (d, J_(CF)=7.5 Hz), 30.3 (d,J_(CF)=22.5 Hz), 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₁₈H₂₁ClFN₂O₃: 403.0986, found 403.0985.

Example 26 Preparation of3-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)-2-chlorophenoxy)propyl4-methylbenzenesulfonate Part A—Preparation of3-chloro-4-(3-hydroxypropoxy)benzaldehyde

A suspension of 3-chloro-4-hydroxybenzaldehyde (0.500 g, 3.20 mmol),1-bromopropanol (0.271 mL, 3.0 mmol), and cesium carbonate (2.44 g, 7.50mmol) in dimethylformamide (32.0 mL) was heated to 60° C. and maintainedovernight. After cooling to ambient temperature, the resulting mixturewas diluted with water (150 mL) and the aqueous layer was extracted withethyl acetate (3×150 mL). The combined organic layers were washed withwater, saturated aqueous sodium chloride, dried over sodium sulfate,filtered and concentrated to a yellow oil (0.322 g, 46.9% yield). ¹H NMR(CDCl₃, 300 MHz): δ 9.77 (s, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.68 (dd,J=8.5, 2.0 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.22 (t, J=5.9 Hz, 2H), 4.15(t, J=5.7 Hz, 2H), 2.11-2.03 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz): δ 189.8,159.1, 131.2, 130.6, 130.3, 123.8, 112.4, 67.2, 60.0, 31.6.

Part B—Preparation of4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-chlorophenyl)methanol

A solution of the product of Example 26A (0.312 g, 1.45 mmol), indimethylformamide (14.5 mL) was successively treated withtert-butyldimethylsilyl chloride (0.329 g, 2.18 mmol) and imidazole(0.149 g, 2.18 mmol) at ambient temperature then stirred overnight. Theresulting mixture was diluted with 0.1 N hydrochloric acid (30 mL) thenextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material wasthen purified by silica gel chromatography (0-50% ethyl acetate inhexanes) to afford the desired product as a clear oil (0.167 g, 35.0%yield). ¹H NMR (CDCl₃, 300 MHz): δ 9.81 (s, 1H), 7.87 (d, J=2.1 Hz, 1H),7.72 (dd, J=8.5, 2.1 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 4.20 (t, J=6.1 Hz,2H), 3.81 (t, J=5.8 Hz, 2H), 2.07-1.99 (m, 2H), 0.84 (s, 9H), 0.01 (s,6H); ¹³C NMR (CDCl₃, 75 MHz): δ 189.7, 159.4, 131.2, 130.5, 130.1,124.0, 112.5, 65.9, 65.8, 59.0, 32.0, 25.9, 18.3, −5.5; HRMS-TOF (m/z):[M+H]⁺ for C₁₆H₂₅ClO₃Si: 329.1334, found 329.1329.

A solution of the silyl ether (0.176 g, 0.536 mmol) in ethanol (6.00 mL)was treated with sodium borohydride (15.2 mg, 0.402 mmol) in one portionat ambient temperature then stirred overnight. The resulting mixture wasthen diluted with water (10 mL) and concentrated in vacuo to remove theethanol. The resulting aqueous solution was extracted with ethyl acetate(3×50 mL) and the combined organic layers dried over sodium sulfate,filtered and concentrated to afford the desired product as an oil (0.164g, 92.5% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.34 (d, J=2.2 Hz, 1H), 7.16(dd, J=8.3, 2.2 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.57 (s, 2H), 4.09 (t,J=6.1 Hz, 2H), 3.80 (t, J=5.9 Hz, 2H), 2.03-1.95 (m, 2H), 0.84 (s, 9H),0.01 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 154.1, 133.7, 129.2, 126.5,123.0, 113.2, 65.6, 64.5, 59.3, 32.2, 25.9, 18.5, −5.4; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₆H₂₇ ³⁵CO₃Si: 331.1491, found 331.1493.

Part C—Preparation of2-(tert-butyl)-5-((4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-chlorobenzyl)oxy)-4-chloropyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridazin-3(2H)-one (82.8mg, 0.410 mmol) in tetrahydrofuran (4.90 mL) was successively treatedwith the product of Example 27B (0.162 g, 0.490 mmol),triphenylphosphine (0.161 g, 0.615 mmol), and diethylazodicarboxylate(0.107 g, 0.615 mmol) at ambient temperature. After 20 min, theresulting mixture was diluted with water (5 mL), the aqueous layerseparated then extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified by silicagel chromatography (0-10% gradient ethyl acetate in hexanes) to affordthe desired product as a clear oil (0.127 g, 60.1% yield). ¹H NMR(CDCl₃, 300 MHz): δ 7.67 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.21 (dd,J=2.3, 8.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.17 (s, 2H), 4.11 (t, J=6.1Hz, 2H), 3.80 (t, J=5.9 Hz, 2H), 2.04-1.96 (m, 2H), 1.60 (s, 9H), 0.84(s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.0, 155.0, 153.6,129.3, 127.6, 127.0, 125.1, 123.3, 118.5, 113.3, 71.1, 66.4, 65.6, 59.2,32.2, 27.9, 25.9, 18.3, −5.4.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((3-chloro-4-(3-hydroxypropoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 27C (0.127 g, 0.246 mmol), intetrahydrofuran (2.5 mL) was treated with tetrabutylammonium fluoride(0.49 mL, 0.49 mmol, of a 1 M solution in tetrahydrofuran) at ambienttemperature. After 40 min, the resulting mixture was diluted with water(5 mL), the aqueous layer separated then extracted with ethyl acetate(2×20 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was thenpurified by silica gel chromatography (0-80% ethyl acetate in hexanes)to afford the desired product (71.6 mg, 72.5% yield). ¹H NMR (CDCl₃, 300MHz): δ 7.63 (s, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.21 (dd, J=8.5, 3.0 Hz,1H), 6.90 (d, J=8.5 Hz, 1H), 5.14 (s, 2H), 4.15 (t, J=5.8 Hz, 2H), 3.84(t, J=5.7 Hz, 2H), 2.08-1.99 (m, 2H), 1.57 (s, 9H); ¹³C NMR (CDCl₃, 75MHz): δ 159.0, 154.6, 153.5, 129.3, 128.1, 127.0, 125.1, 123.3, 118.6,113.3, 71.0, 67.4, 66.5, 60.5, 31.7, 27.9; HRMS-TOF (m/z): [M+H]⁺ forC₁₈H₂₂ ³⁵Cl₂N₂O₄: 401.1029, found 401.1023.

Part E—Preparation of3-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)-2-chlorophenoxy)propyl4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 27D(35.8 mg, 0.089 mmol), p-toluenesulfonyl chloride (20.5 mg, 0.107 mmol),4-dimethylaminopyridine (16.3 mg, 0.13 mmol), and diisopropylethylamine(0.015 mL, 0.107 mmol). Isolated yield—29.8 mg; 60.3%. ¹H (CDCl₃, 300MHz): δ 7.68 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 7.31 (d, J=2.2 Hz, 2H),7.17 (m, 1H), 7.15 (d, J=8.3 Hz, 2H), 5.13 (s, 2H), 4.22 (t, J=5.9 Hz,2H), 3.95 (t, J=5.7 Hz, 2H), 2.27 (s, 3H), 2.14-2.07 (m, 2H), 1.57 (s,9H); ¹³C (CDCl₃, 75 MHz): δ 159.0, 154.4, 153.5, 144.8, 132.7, 129.8,129.4, 128.1, 127.8, 127.0, 125.0, 123.5, 118.3, 113.28, 71.0, 66.7,66.5, 64.2, 28.8, 27.9, 21.6; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₂₅H₂₈ ³⁵Cl₂N₂O₆S: 555.1118, found 555.1138.

Example 27 Preparation of2-(tert-butyl)-4-chloro-5-((3,5-dichloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (3,5-dichloro-4-(3-fluoropropoxy)phenyl)methanol

Prepared according to General Method F, using3,5-dichloro-4-hydroxybenzaldehyde (0.860 g, 4.50 mmol), 3-fluoropropylp-toluenesulfonate (1.00 g, 4.29 mmol), and cesium carbonate (2.49 g,7.64 mmol) in dimethylformamide (45.0 mL) at 65° C. ¹HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₀H₉Cl₂FO₂: 251.0036, found 251.0038.

A solution of the crude aldehyde (1.32 g, 5.26 mmol) in ethanol (5.26mL) was treated with sodium borohydride (0.149 g, 3.94 mmol) in oneportion at ambient temperature. After 3 d, the resulting mixture wasdiluted with water (20 mL) and concentrated in vacuo to remove theethanol. The resulting aqueous solution was extracted with ethyl acetate(3×50 mL) and the combined organic layers dried over sodium sulfate,filtered and concentrated to afford the desired product as a clear oil(1.21 g, 90.9% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.24 (s, 2H), 4.76 (t,J=5.8 Hz, 1H), 4.61 (t, J=5.8 Hz, 1H), 4.56 (s, 2H), 4.07 (t, J=6.0 Hz,2H), 2.20 (m, 1H), 2.13 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 150.4,138.3, 129.5, 127.2, 81.4 (d, J_(CF)=165 Hz), 69.2 (d, J_(CF)=7.5 Hz),63.7, 31.2 (d, J_(CF)=22.5 Hz).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((3,5-dichloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.195 g, 0.872 mmol),the product of Example 27A (0.138 g, 0.545 mmol), and cesium carbonate(0.213 g, 0.654 mmol) in dimethylformamide (8.50 mL) at 65° C. Isolatedyield—0.192 g; 80.5% ¹H NMR (CDCl₃, 300 MHz): δ 7.61 (s, 1H), 7.29 (s,2H), 5.12 (s, 2H), 4.76 (t, J=5.8 Hz, 1H), 4.58 (t, J=5.8 Hz, 1H), 4.10(t, J=6.0 Hz, 2H), 2.20 (m, 1H), 2.14 (m, 1H), 1.57 (s, 9H); HRMS:Calcd. for C₁₈H₂₀ ³⁵Cl₃FN₂O₃: 437.0596, found 437.0609.

Example 28 Preparation of5-((3-bromo-4-(3-fluoropropoxy)-5-methoxybenzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-onePart A—Preparation of 3-bromo-4-(3-fluoropropoxy)-5-methoxybenzaldehyde

3-Bromo-4-hydroxy-5-methoxybenzaldehyde (0.578 g, 2.50 mmol),triphenylphosphine (0.820 g, 3.13 mmol) and 3-fluoropropan-1-ol (0.244mL, 3.25 mmol) were combined in dry tetrahydrofuran (12.5 mL), thencooled to 0° C. and treated with diethyl azodicarboxylate (0.472 mL,3.00 mmol) dropwise over 0.25 h. After 0.25 h, the resulting solutionwas warmed to ambient temperature and maintained an additional 0.25 h.All volatiles were then removed in vacuo and the residue directlypurified by chromatography on silica (50×155 mm) using 3:1pentane/diethyl ether. The main product peak eluting 700-1200 mL wascollected, pooled and concentrated in vacuo to a colorless oil (0.555 g,1.91 mmol; 76.3%). ¹H NMR: (300 MHz, CDCl₃) δ 9.84 (1H, s), 7.65 (1H, d,J=1.8 Hz), 7.38 (1H, d, J=1.8 Hz), 4.75 (2H, dt, J=47.0, 5.8 Hz), 4.24(2H, t, J=6.0 Hz), 3.92 (3H, s), 2.19 (2H, dtt, J=25.7, 5.9, 5.9 Hz).¹³C NMR: (75 MHz, CDCl₃) δ 189.8, 154.1, 150.8, 133.0, 128.8, 118.0,110.0, 80.8 (d, J_(CF)=164 Hz), 69.2 (d J_(CF)=5.4 Hz), 56.2, 31.3 (d,J_(CF)=20.2 Hz). ¹⁹F NMR (282 MHz, CDCl₃) δ −222.0 (tt, J=46.9, 25.7Hz). HRMS Calcd. for ClH₁₂ ⁷⁹BrFO₃ (M+H): 291.0027; found: 291.0030.TLC: R_(f) 0.26 (silica gel, 3:1 pentane/diethyl ether, KMnO₄).

Part B—Preparation of5-((3-bromo-4-(3-fluoropropoxy)-5-methoxybenzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2-one

A solution of the product of part A (0.146 g, 0.500 mmol) in wetmethanol (5.00 mL) was cooled to 0° C. then treated with sodiumborohydride (37.8 mg, 1.00 mmol) in one portion. After 0.25 h, excesssodium borohydride was consumed by the dropwise addition of saturatedaqueous ammonium chloride (2 mL), and the resulting solution warmed toambient temperature. After 0.5 h, the resulting mixture was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate (25 mLeach), with transfer to a separatory funnel, and the layers separated.The aqueous layer was then washed with ethyl acetate (2×25 mL), and thecombined ethyl acetate washes dried over magnesium sulfate, filtered andconcentrated in vacuo to a colorless oil.

The crude oil thus obtained was dissolved in dry dimethylformamide (5.00mL) then successively treated with2-(tert-butyl)-4,5-dichloro-2-hydropyridazin-3-one³ (0.166 g, 0.750mmol) and cesium carbonate (0.326, 1.00 mmol) in one portion at ambienttemperature. The resulting suspension was then immersed in a pre-heatedoil bath, and maintained at 65° C., with vigorous stirring, 21 h. Aftercooling to ambient temperature, the suspension was partitioned betweenethyl acetate and water (20 mL each), with transfer to a separatoryfunnel, and the layers separated. The aqueous layer was then washed withethyl acetate (2×20 mL) and the combined ethyl acetate washes dried overmagnesium sulfate, filtered and concentrated in vacuo to an amber oil.The crude material was then purified by chromatography on silica (30×180mm) using 7:3 pentane/ethyl acetate. The main product peak eluting200-350 mL was collected, pooled and concentrated in vacuo to a whitesolid (0.191 g, 0.400 mmol; 79.9%). ¹H NMR: (300 MHz, CDCl₃) δ 7.71 (1H,s), 7.15 (1H, d, J=1.9 Hz), 6.92 (1H, d, J=2.0 Hz), 5.21 (2H, s), 4.74(2H, dt, J=47.1, 5.9 Hz), 4.13 (2H, t, J=6.0 Hz), 3.86 (3H, s), 2.17(2H, dtt, J=25.5, 6.0, 6.0 Hz), 1.64 (9H, s). ¹³C NMR: (75 MHz, CDCl₃) δ158.9, 154.1, 153.4, 145.8, 131.9, 125.0, 123.2, 118.6, 118.0, 110.2,81.0 (d, J_(CF)=164 Hz), 71.0, 68.9 (d, J_(CF)=5.5 Hz), 66.5, 56.1, 31.3(d, J_(CF)=20.2 Hz), 27.8. HRMS Calcd. for C₉H23⁷⁹Br³⁵ClN₂O₄ (M+H):477.0587; found: 477.0589. TLC: R_(f) 0.15 (silica gel, 4:1pentane/ethyl acetate, CAM).

Example 29 Preparation of2-(tert-butyl)-4-chloro-5-((2-chloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (2-chloro-4-(3-fluoropropoxy)phenyl)methanol

Prepared according to General Method F, using methyl2-chloro-4-hydroxybenzoate (0.354 g, 2.26 mmol), 3-fluoropropylp-toluenesulfonate (0.500 g, 2.15 mmol), and cesium carbonate (1.12 g,3.44 mmol) in dimethylformamide (22.6 mL) at 60° C. Isolated yield—0.510g). ¹H NMR (CDCl₃, 300 MHz): δ 7.81 (d, J=8.9 Hz, 1H), 6.90 (d, J=2.5Hz, 1H), 6.75 (dd, J=8.8, 2.5 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 4.49 (t,J=5.8 Hz, 1H), 4.07 (t, J=6.1 Hz, 2H), 3.82 (s, 3H), 2.16 (m, 1H), 2.09(m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 165.5, 161.7, 135.9, 133.4, 121.8,117.0, 112.9, 80.3 (d, J_(CF)=165 Hz), 64.1 (d, J_(CF)=7.5 Hz), 52.1,30.2 (d, J_(C)=22.5 Hz).

A solution of the alcohol (0.510 g, 2.35 mmol) in ethanol (23.5 mL) wastreated with sodium borohydride (66.7 mg, 1.76 mmol) in one portion atambient temperature then stirred overnight. The resulting mixture wasdiluted with water (20 mL) and concentrated in vacuo to remove theethanol. The resulting aqueous solution was extracted with ethyl acetate(3×50 mL) and the combined organic layers dried over sodium sulfate,filtered and concentrated to afford the desired product as a clear oil(0.388 g, 78.5% yield). ¹H NMR (CDCl₃, 300 MHz): δ7.80 (d, J=8.8 Hz,1H), 6.90 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8.8, 2.5 Hz, 1H), 4.64 (t,J=6.4 Hz, 1H), 4.65 (s, 2H), 4.49 (t, J=5.8 Hz, 1H), 4.07 (t, J=6.2 Hz,2H), 2.16 (m, 1H), 2.09 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.9,135.8, 133.3, 130.1, 117.0, 112.8, 80.3 (d, J_(CF)=165 Hz), 64.1 (d,J_(CF)=7.5 Hz), 61.1, 30.2 (d, J_(CF)=22.5 Hz); ¹HRMS-TOF (m/z): [M−H]⁺HRMS: Calcd. for C₁₀H₁₂ ³⁵ClFO₂: 217.0437, found 217.0453.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((2-chloro-4-(3-fluoropropoxy) benzyl) oxy)pyridazin-3 (2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.358 g, 1.62 mmol),the product of Example 29A, (0.388 g, 1.78 mmol), and cesium carbonate(0.845 g, 2.59 mmol) in dimethylformamide (16.2 mL) at 60° C. Isolatedyield—0.251 g; 38.4% yield. ¹H NMR (CDCl₃, 300 MHz): δ 7.67 (s, 1H),7.35 (d, J=8.6 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 6.79 (dd, J=8.7, 2.5 Hz,1H), 5.26 (s, 2H), 4.65 (t, J=5.7 Hz, 1H), 4.49 (t, J=5.7 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 2.15 (m, 1H), 2.06 (m, 1H), 1.57 (s, 9H); ¹³C NMR(CDCl₃, 75 MHz): δ 159.7, 153.6, 133.7, 130.1, 125.2, 124.7, 118.5,115.8, 113.7, 80.3 (d, J_(CF)=165 Hz), 68.9, 66.4, 64.0 (d, J_(CF)=7.5Hz), 30.4, 30.1, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₈H₂₁³⁵Cl₂FN₂O₃: 403.0986, found 403.0994.

Example 30 Preparation of2-(tert-butyl)-4-chloro-5-((4-(3-fluoropropoxy)-2-methylbenzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (4-(3-fluoropropoxy)-2-methylphenyl)methanol

Prepared according to General Method F, using4-hydroxy-2-methylbenzaldehyde (0.614 g, 4.50 mmol), 3-fluoropropylp-toluenesulfonate (1.00 g, 4.29 mmol), and cesium carbonate (2.49 g,7.64 mmol) in dimethylformamide (45.0 mL) at 60° C. ¹H NMR (CDCl₃, 300MHz): δ 10.13 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 6.86 (dd, J=8.6, 4.6 Hz,1H), 6.77 (d, J=2.3 Hz, 1H), 4.75 (t, J=5.7 Hz, 1H), 4.59 (t, J=5.7 Hz,1H), 4.18 (t, J=6.1 Hz, 2H), 2.66 (s, 3H), 2.27 (m, 1H), 2.15 (m, 1H);HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₁H₁₃FO₂: 197.0976, found197.0972.

A cooled (0° C.) solution of 4-(3-fluoropropoxy)-2-methylbenzaldehyde(0.840 g, 4.28 mmol) in tetrahydrofuran (42.8 mL) was treated withlithium aluminum hydride (2.14 mL, 2.14 mmol, of 1 M tetrahydrofuransolution) then warmed to ambient temperature. The resulting mixture wasstirred overnight then diluted with water (20 mL). The aqueous layer wasthen separated and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto a dark orange oil (0.800 g, 94.3% yield). ¹H NMR (CDCl₃, 300 MHz): δ7.24 (m, 1H), 6.73 (m, 2H), 4.72 (t, J=5.8 Hz, 1H), 4.63 (s, 2H), 4.56(t, J=5.8 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.36 (s, 3H), 2.20 (m, 1H),2.10 (m, 1H).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(3-fluoropropoxy)-2-methylbenzyl) oxy)pyridazin-3 (2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.480 g, 2.37 mmol),the product of Example 30A, (0.940 g, 4.74 mmol), and cesium carbonate(1.70 g, 5.28 mmol) in dimethylformamide (24.0 mL) at 65° C. overnight.Isolated yield—38.6 mg; 4.3% yield. ¹H NMR (CDCl₃, 300 MHz): δ 7.50 (s,1H), 7.19 (m, 1H), 6.66 (m, 2H), 5.09 (s, 2H), 4.64 (m, 1H), 4.48 (m,1H), 4.02 (t, J=6.2 Hz, 2H), 2.27 (s, 3H), 2.14 (m, 1H), 2.03 (m, 1H),1.57 (s, 9H); HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₉H₂₄ ³⁵ClFN₂O₃:386.1532, found 383.1537.

Example 31 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)-2-methoybenzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of methyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)-3-methoxybenzoate

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (0.617 g, 3.05mmol), methyl 4-(bromomethyl)-3-methoxybenzoate (0.750 g, 2.91 mmol),and cesium carbonate (1.51 g, 4.64 mmol) in dimethylformamide (15.0 mL)at ambient temperature. Isolated yield—1.11 g; >98%. ¹H NMR (CDCl₃, 300MHz): δ 7.65 (s, 1H), 7.63 (dd, J=7.9, 1.4 Hz, 1H), 7.51 (d, J=1.4 Hz,1H), 7.44 (d, J=7.9 Hz, 1H), 5.30 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H),1.57 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 166.6, 159.0, 156.3, 153.7,131.6, 128.4, 127.7, 125.0, 122.4, 118.2, 111.1, 66.7, 66.4, 55.7, 52.3,27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₈H₂₁ ³⁵ClN₂O₅: 381.1212,found 381.1206.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(hydroxymethyl)-2-methoxybenzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 31A (1.11 g, 2.92 mmol), intetrahydrofuran (29.0 mL) at 0° C. was treated with lithium aluminumhydride (1.46 mL, 1.46 mmol, 1 M solution in tetrahydrofuran) thenwarmed to ambient temperature. The resulting mixture was stirredovernight then diluted with water (50 mL). The aqueous layer wasseparated then extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto an amorphous orange solid (0.890 g, 86.4% yield). ¹H NMR (CDCl₃, 300MHz): δ 7.68 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.89 (m, 2H), 5.27 (s,2H), 4.64 (s, 2H), 3.85 (s, 3H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz):δ 159.1, 156.9, 153.9, 143.2, 128.7, 125.4, 122.5, 119.1, 118.0, 109.1,67.0, 66.3, 65.1, 55.5, 27.9; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. forC₁₇H₂₁ ³⁵ClN₂O₄: 353.1263, found 353.1257.

Part C—Preparation of5-((4-(bromomethyl)-2-methoxybenzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

Prepared according to General Method C, using the product of Example 31B(0.448 g, 1.26 mmol) and phosphorous tribromide (0.631 mL, 0.63 mmol, 1M in dichloromethane). Isolated yield—0.429 g; 81.9%. ¹H NMR (CDCl₃, 300MHz): δ 7.67 (s, 1H), 7.32 (d, J=7.7 Hz, 1H), 6.98 (dd, J=7.7, 1.6 Hz,1H), 6.88 (d, J=1.5 Hz, 1H), 5.25 (s, 2H), 4.42 (s, 2H), 3.82 (s, 3H),1.57 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.1, 156.7, 153.8, 139.6,128.7, 125.2, 123.7, 121.5, 118.1, 111.1, 66.8, 66.3, 55.6, 33.1, 27.9;HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₇H₂₀ ⁷⁹Br³⁵ClN₂O₃: 415.0419,found 415.0416.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)-2-methoxybenzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method E, using potassium tert-butoxide(38 mg, 0.340 mmol), 2-fluoroethanol (14.5 mg, 0.226 mmol) and theproduct of Example 31C (0.112 g, 0.271 mmol). Isolated yield—2.3 mg;2.6%. ¹H NMR (CDCl₃, 300 MHz): δ 7.68 (s, 1H), 7.30 (d, J=7.5 Hz, 1H),6.9 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.27 (s, 2H), 4.62 (m, 1H), 4.53(s, 2H), 4.46 (m, 1H), 3.82 (s, 3H), 3.73 (m, 1H), 3.63 (m, 1H), 1.56(s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.1, 155.8, 152.9, 139.1, 127.5,124.3, 121.7, 119.0, 117.0, 108.6, 82.1 (d, J_(CF)=165 Hz), 72.0, 68.5(d, J_(CF)=22.5 Hz), 65.9, 65.3, 54.5, 26.9; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₁₉H₂₄ ³⁵ClFN₂O₃: 399.1481, found 399.1479.

Example 32 Preparation of2-(tert-butyl)-4-chloro-5-((3-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (3-(3-fluoropropoxy)phenyl)methanol

Prepared according to General Method F, using 3-hydroxybenzaldehyde(0.552 g, 4.52 mmol), 3-fluoropropyl p-toluenesulfonate (0.998 g, 4.30mmol), and cesium carbonate (2.24 g, 6.90 mmol) in dimethylformamide(45.2 mL) at 60° C. Isolated yield—0.700 g; 89.4%. ¹H NMR (CDCl₃, 300MHz): δ 9.91 (s, 1H), 7.40-7.37 (m, 2H), 7.34 (m, 1H), 7.11 (m, 1H),4.66 (t, J=5.8 Hz, 1H), 4.52 (t, J=5.7 Hz, 1H), 4.10 (t, J=6.1 Hz, 2H),2.17 (m, 1H), 2.09 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 192.0, 159.4,137.9, 130.1, 123.6, 121.8, 113.0, 80.5 (d, J_(CF)=165 Hz), 63.9 (d,J_(C)=7.5 Hz), 30.3 (d, J_(C)=22.5 Hz). ¹HRMS-TOF (m/z): [M+H]⁺ HRMS:Calcd. for C₁₀H₁₁FO₂: 183.0816, found 183.0827.

A cooled (0° C.) solution of 3-(3-fluoropropoxy) benzaldehyde (0.700 g,3.82 mmol) dissolved in ethanol (38 mL) was treated with sodiumborohydride (72.3 mg, 1.91 mmol) then warmed to ambient temperature.After 2 h, the resulting mixture was diluted with water (20 mL) andconcentrated in vacuo to remove the ethanol. The resulting aqueoussolution was extracted with ethyl acetate (3×50 mL) and the combinedorganic layers dried over sodium sulfate, filtered and concentrated toafford the desired product as a yellow oil (0.625 g, 88.8% yield). ¹HNMR (CDCl₃, 300 MHz): δ 7.20 (m, 1H), 6.87 (m, 2H), 6.76 (dd, J=8.3, 2.1Hz, 1H), 4.65 (t, J=5.8 Hz, 1H), 4.60 (s, 2H), 4.50 (t, J=5.8 Hz, 1H),4.04 (t, J=6.1 Hz, 2H), 2.14 (m, 1H), 2.04 (m, 1H); ¹³C NMR (CDCl₃, 75MHz): δ 159.1, 142.6, 129.6, 119.3, 113.8, 113.0, 80.7 (d, J_(CF)=165Hz), 65.2, 63.5 (d, J_(CF)=7.5 Hz), 30.6 (d, J_(CF)=22.5 Hz). ¹HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₁₀H₁₃FO₂: 185.0972, found 186.0967.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((3-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using of2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.339 g, 1.53 mmol),the product of Example 32A (0.313 g, 1.69 mmol), and cesium carbonate(0.798 g, 2.45 mmol) in dimethylformamide (17.0 mL) at 60° C. Isolatedyield—0.122 g, 21.6% yield. ¹H NMR (CDCl₃, 300 MHz): δ 7.63 (s, 1H),7.25 (m, 1H), 6.92-6.81 (m, 3H), 5.21 (s, 2H), 4.66 (t, J=5.8 Hz, 1H),4.50 (t, J=5.8 Hz, 1H), 4.04 (t, J=6.1 Hz, 2H), 2.15 (m, 1H), 2.07 (m,1H), 1.57 (s, 9H); (CDCl₃, 75 MHz): δ 159.3, 159.0, 153.7, 136.5, 130.1,125.1, 119.3, 118.4, 114.7, 113.9, 80.6 (d, J_(CF)=165 Hz), 71.7, 66.4,63.6 (d, J_(CF)=7.5 Hz), 30.4 (d, J_(CF)=22.5 Hz), 27.9; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₈H₂₂ ³⁵ClFN₂O₃: 369.1376, found 369.1379.

Example 33 Preparation of2-(tert-butyl)-4-chloro-5-((3-(2-fluoroethoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (3-(2-fluoroethoxy)phenyl)methanol

A suspension of 3-hydroxybenzaldehyde (1.02 g, 8.33 mmol),1-bromo-2-fluoroethane (1.00 g, 7.93 mmol), and cesium carbonate (4.13g, 12.7 mmol) in dimethylformamide (83.0 mL) was heated to 60° C. andmaintained overnight. After cooling to ambient temperature, theresulting mixture was diluted with water (100 mL), and the aqueous layerextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with water (150 mL) and saturated aqueous sodium chloride(150 mL) then dried over sodium sulfate, filtered and concentrated to anorange oil (1.34 g). ¹H NMR (CDCl₃, 300 MHz): δ 9.91 (s, 1H), 7.44-7.33(m, 3H), 7.19-7.13 (m, 1H), 4.79 (m, 1H), 4.63 (m, 1H), 4.26 (m, 1H),4.17 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 192.0, 159.0, 137.9, 130.2,124.1, 122.2, 112.7, 81.9 (d, J_(CF)=165 Hz), 67.4 (d, J_(CF)=22.5 Hz);¹HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₉H₉FO₂: 169.0659, found169.0660.

A cooled (0° C.) solution of the aldehyde (1.34 g) in ethanol (39.5 mL)was treated with sodium borohydride (0.150 g, 3.97 mmol) in one portionthen warmed to ambient temperature. After 2 h, the resulting mixture wasdiluted with water (20 mL) and concentrated in vacuo to remove theethanol. The resulting aqueous solution was extracted with ethyl acetate(3×50 mL) and the combined organic layers dried over sodium sulfate,filtered and concentrated to afford the desired product as a yellow oil(1.28 g, 94.8% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.20 (m, 1H), 6.89 (m,2H), 6.78 (m, 1H), 4.75 (m, 1H), 4.60 (s, 2H), 4.59 (m, 1H), 4.20 (m,1H), 4.10 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.7, 142.7, 129.7,119.7, 114.0, 113.0, 81.9 (d, J_(CF)=165 Hz), 67.2 (d, J_(CF)=22.5 Hz),65.2; ¹HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₉H₁₁FO₂: 171.0816, found171.0815.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((3-(2-fluoroethoxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.587 g, 2.66 mmol),the product of Example 33A, (0.500 g, 2.92 mmol), and cesium carbonate(1.38 g, 4.25 mmol) in dimethylformamide (26.6 mL) at 60° C. Isolatedyield—20 mg, 2.1% yield. ¹H NMR (CDCl₃, 300 MHz): δ 7.63 (s, 1H), 7.26(m, 1H), 6.95-6.84 (m, 3H), 5.22 (s, 2H), 4.78 (m, 1H), 4.62 (m, 1H),4.21 (m, 1H), 4.11 (m, 1H), 1.56 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz): δ159.0, 158.9, 153.6, 136.6, 130.2, 125.1, 119.3, 114.9, 114.8, 113.2,81.9 (d, J_(CF)=7.5 Hz), 71.6, 67.2 (d, J_(CF)=22.5 Hz), 66.4, 27.9.HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₇H₂₀ ³⁵ClFN₂O₃: 355.1219,found 355.1218.

Example 34 Preparation of2-(3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenoxy)ethyl4-methylbenzenesulfonate Part A—Preparation of3-(2-hydroxyethoxy)benzaldehyde

A suspension of 3-hydroxybenzaldehyde (1.02 g, 8.33 mmol),1-bromoethanol (0.991 g, 7.93 mmol), and cesium carbonate (4.13 g, 12.7mmol) in dimethylformamide (20.0 mL) was heated to 60° C. and maintainedovernight. After cooling to ambient temperature, the resulting mixturewas diluted with water (50 mL), and the aqueous layer extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (150 mL) and saturated aqueous sodium chloride then dried oversodium sulfate, filtered and concentrated to yield a yellow oil. Thecrude material was then purified by silica gel chromatography 4:1hexanes/ethyl acetate to afford the desired product as a white solid(1.38 g, >98% yield). ¹H NMR (CDCl₃, 300 MHz): δ 9.98 (s, 1H), 7.48-7.41(m, 3H), 7.23-7.19 (m, 1H), 4.16 (m, 2H), 4.00 (m, 2H); HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₉H₁₀O₃: 167.0703, found 167.0696.

Part B—Preparation of(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)methanol

A solution of the product of Example 34A (1.38 g), in dimethylformamide(8.3 mL) was successively treated with tert-butyldimethylsilyl chloride(1.88 g, 12.5 mmol) and imidazole (0.850 g, 12.5 mmol) then stirred atambient temperature overnight. The resulting mixture was then dilutedwith water (50 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over sodium sulfate, filtered, and concentrated in vacuoto a yellow oil (0.597 g, 26.8% yield). ¹H NMR (CDCl₃, 300 MHz): δ 9.87(s, 1H), 7.35-7.29 (m, 3H), 7.11-7.08 (m, 1H), 4.00 (m, 2H), 3.89 (m,2H), 0.84 (s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 189.7,159.4, 137.8, 130.0, 123.5, 122.0, 113.0, 69.6, 61.9, 25.6, 18.4, −5.2;HRMS-TOF (m/z): [M+H]⁺ for C₁₅H₂₀O₃Si: 281.1567, found 281.1563.

A solution of the silyl ether (0.597 g, 2.13 mmol) in ethanol (21.0 mL)was treated with sodium borohydride (60.4 mg, 1.60 mmol) in one portionat ambient temperature. After 3 h, the resulting mixture was dilutedwith water (10 mL) and concentrated in vacuo to remove the ethanol. Theresulting aqueous solution was extracted with ethyl acetate (3×50 mL)and the combined organic layers dried over sodium sulfate, filtered andconcentrated to afford the desired product as a milky white oil (0.600g, >98% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.16 (m, 1H), 6.84 (m, 2H),6.74 (dd, J=9.0, 2.5 Hz, 1H), 4.57 (s, 2H), 3.94 (m, 2H), 3.87 (m, 2H),0.81 (s, 9H), 0.01 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.3, 142.5,129.6, 119.1, 114.0, 113.0, 69.3, 65.3, 62.0, 25.6, 18.4, −5.2; HRMS-TOF(m/z): [M+H]⁺ HRMS: Calcd. for C₁₅H₂₆O₃Si: 283.1724, found 283.1717.

Part C—Preparation of2-(tert-butyl)-5-((3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzyl)oxy)-4-chloropyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.711 g, 3.19 mmol),the product of Example 34B (0.600 g, 2.13 mmol), and cesium carbonate(0.834 g, 2.56 mmol) in dimethylformamide (32.0 mL) at 60° C. Isolatedyield—0.159 g, 16.0% yield. ¹H NMR (CDCl₃, 300 MHz): δ 7.62 (s, 1H),7.21 (m, 1H), 6.82-6.79 (m, 3H), 5.19 (s, 2H), 3.95 (m, 2H), 3.88 (m,2H), 1.53 (s, 9H), 0.80 (s, 9H), −0.01 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz):δ 159.5, 159.0, 153.7, 136.5, 130.0, 125.1, 119.1, 118.2, 114.8, 113.2,71.7, 69.4, 66.4, 62.0, 27.9, 25.9, 18.4, −5.2; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₂₃H₃₅ ³⁵ClN₂O₄Si: 467.2127, found 467.2129.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((3-(2-hydroxyethoxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 34C (0.140 g, 0.300 mmol), intetrahydrofuran (3.0 mL) was treated with tetrabutylammonium fluoride(0.60 mL, 0.60 mmol, of 1 M solution in tetrahydrofuran) at ambienttemperature. After 1 h, the resulting mixture was diluted with water (10mL), the aqueous layer separated then extracted with ethyl acetate (2×20mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was thenpurified by silica gel chromatography (20-50% ethyl acetate in hexanes)to afford the desired product (0.105 g, >98% yield). ¹H NMR (CDCl₃, 300MHz): δ 7.57 (s, 1H), 7.16 (m, 1H), 6.83 (m, 2H), 6.76 (dd, J=7.5, 2.0Hz, 1H), 5.13 (s, 2H), 3.95 (m, 2H), 3.82 (m, 2H), 1.47 (s, 9H); ¹³C NMR(CDCl₃, 75 MHz): δ 159.1, 159.0, 153.6, 136.5, 130.0, 125.0, 119.3,118.2, 114.6, 113.1, 71.5, 69.2, 66.4, 61.2, 27.8; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₇H₂₁ ³⁵ClN₂O₄: 353.1263, found 353.1259.

Part E—Preparation of2-(3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)phenoxy)ethyl4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 34D(52.4 mg, 0.149 mmol), p-toluenesulfonyl chloride (34.1 mg, 0.179 mmol),4-dimethylaminopyridine (22.0 mg, 0.179 mmol), and diisopropylethylamine(0.032 mL, 0.179 mmol). Isolated yield—48.5 mg, 64.2% yield. ¹H (CDCl₃,300 MHz): δ 7.75 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.29-7.20 (m, 3H),6.92 (d, J=7.1 Hz, 1H), 6.79 (m, 1H), 6.72 (dd, J=8.2, 2.0 Hz, 1H), 5.19(s, 2H), 4.30 (m, 2H), 4.09 (m, 2H), 2.38 (s, 3H), 1.56 (s, 9H); ¹³C NMR(CDCl₃, 75 MHz): δ 158.0, 157.5, 152.6, 144.0, 135.6, 131.8, 129.1,128.9, 127.0, 124.0, 118.8, 117.3, 113.8, 112.1, 70.5, 66.9, 65.4, 64.5,26.8, 20.6. HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₄H₂₇ ³⁵ClN₂O₆S:507.1351, found 507.1354.

Example 35 Preparation of2-(tert-butyl)-4-chloro-5-((3-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of methyl3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methylbenzoate

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (0.750 g, 3.70mmol), methyl 4-(bromomethyl)benzoate (0.806 g, 3.52 mmol), and cesiumcarbonate (1.45 g, 4.45 mmol) in dimethylformamide (7.5 mL) at ambienttemperature. Isolated yield—0.643 g, 52.1% yield. ¹H NMR (CDCl₃, 300MHz): δ 8.01-7.96 (m, 2H), 7.65 (s, 1H), 7.59-7.41 (m, 2H), 5.27 (s,2H), 3.86 (s, 3H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 166.5,159.0, 153.5, 135.4, 131.5, 130.9, 129.2, 128.2, 127.8, 125.0, 118.6,71.4, 66.5, 52.3, 27.9.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((3-(hydroxymethyl)benzyl)oxy)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 35A (0.643 g, 1.83mmol), in tetrahydrofuran (6.5 mL) was treated with lithiumdiisobutylaluminum hydride (2.25 mL, 2.25 mmol, 1 M solution in hexanes)then warmed to ambient temperature and stirred overnight. The resultingsolution was diluted with water (50 mL), the aqueous layer was separatedthen extracted with ethyl acetate (3×150 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo. The crude material was then purified by silica gel chromatography(5-50% ethyl acetate in hexanes) to afford the desired product as awhite solid (0.403 g, 68.2% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.74 (s,1H), 7.45-7.28 (m, 4H), 5.34 (s, 2H), 4.76 (s, 2H), 1.65 (s, 9H); ¹³CNMR (CDCl₃, 75 MHz): δ 159.0, 153.7, 141.8, 135.3, 129.2, 127.3, 126.3,125.5, 125.1, 118.4, 71.8, 66.4, 64.9, 27.9; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₁₆H₁₉ ³⁵ClN₂O₃: 323.1157, found 323.1154.

Part C—Preparation of 5-((3-(bromomethyl) benzyl)oxy)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

Prepared according to General Method C, using the product of Example 35B(0.190 g, 0.590 mmol) and phosphorous tribromide (0.280 mL, 0.29 mmol, 1M in dichloromethane) dropwise. Isolated yield—0.203 g, 89.2% yield. ¹HNMR (CDCl₃, 300 MHz): δ 7.64 (s, 1H), 7.37-7.28 (m, 4H), 5.23 (s, 2H),4.43 (s, 2H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.0, 153.6,138.7, 135.6, 129.3, 129.2, 127.6, 127.1, 125.1, 118.5, 71.5, 66.5,32.8, 27.9; HRMS-TOF (m/z): [M+H]⁺ for C₆H₁₈ ⁷⁹Br³⁵ClN₂O₂: 385.0313,found 385.0316.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((3-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method E, using potassium tert-butoxide(25.9 mg, 0.231 mmol), 2-fluoroethanol (14.8 mg, 0.231 mmol) and theproduct of Example 35C (0.100 g, 0.260 mmol). Isolated yield—2.3 mg;2.7%. ¹H NMR (CDCl₃, 300 MHz): δ 7.65 (s, 1H), 7.37-7.30 (m, 4H), 5.25(s, 2H), 4.62 (m, 1H), 4.55 (s, 2H), 4.46 (m, 1H), 3.73 (m, 1H), 3.64(m, 1H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.1, 153.7, 138.8,135.2, 129.1, 128.0, 126.5, 126.2, 125.1, 118.4, 83.0 (d, J_(CF)=165Hz), 73.0, 71.8, 69.7 (d, J_(CF)=22.5 Hz), 66.4, 28.9; HRMS-TOF (m/z):[M+H]⁺ for C₁₈H₂₂ ³⁵ClFN₂O₃: 369.1376, found 369.1373.

Example 36 Preparation of2-((3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl4-methylbenzenesulfonate Part A—Preparation of2-(tert-butyl)-4-chloro-5-((3-((2-hydroxyethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-one

A suspension of potassium tert-butoxide (25.3 mg, 0.226 mmol) andethylene glycol (111 mg, 1.79 mmol) were heated to 60° C. and maintained20 min. The product of Example 35C (0.104 g, 0.271 mmol), dissolved intetrahydrofuran (3 mL) was added dropwise. After completion of theaddition, the reaction mixture was heated at reflux, maintainedovernight, then cooled and quenched with water (15 mL). The aqueouslayer was separated then extracted with ethyl acetate (3×25 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was then purified by silicagel chromatography using 4:1 hexanes/ethyl acetate to afford the desiredproduct as a clear oil (60.2 mg, 60.6% yield). ¹H NMR (CDCl₃, 300 MHz):δ 7.73 (s, 1H), 7.44-7.29 (m, 4H), 5.32 (s, 2H), 4.59 (s, 2H), 3.78 (m,2H), 3.62 (m, 2H), 1.63 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 159.1,153.7, 139.0, 135.2, 129.2, 128.1, 126.5, 126.2, 125.1, 118.4, 72.9,71.8, 71.6, 66.4, 61.9, 27.9.

Part B—Preparation of2-((3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)ethyl)benzyl)oxy)ethyl4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 36A(50.2 mg, 0.137 mmol), p-toluenesulfonyl chloride (31.3 mg, 0.165 mmol),4-dimethylaminopyridine (21.0 mg, 0.165 mmol), and diisopropylethylamine(0.016 mL, 0.165 mmol). Isolated yield—21.2 mg; 29.7%. ¹H (CDCl₃, 300MHz): δ 7.73 (d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.34-7.19 (m, 6H), 5.23(s, 2H), 4.45 (s, 2H), 4.06 (m, 2H), 3.62 (m, 2H), 2.38 (s, 3H), 1.56(s, 9H); ¹³C (CDCl₃, 75 MHz): δ 159.0, 153.7, 144.9, 138.6, 135.2,133.0, 129.8, 129.1, 127.9, 127.8, 126.5, 126.1, 125.1, 118.3, 72.8,71.8, 69.2, 67.8, 66.4, 27.9, 21.6; HRMS-TOF (m/z): [M+H]⁺ for C₂₅H₂₉³⁵ClN₂O₆S: 521.1508, found 521.1500.

Example 37 Preparation of2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethylmethyl carbonate

A solution of 2-(tert-butyl)-4-chloro-5-((4-((2-hydroxyethoxy)methyl)benzyl) oxy) pyridazin-3(2H)-one (0.147 g, 0.400 mmol; e.g., seeCasebier, David S.; Robinson, Simon P.; Purohit, Ajay; Radeke, Heike S.;Azure, Michael T.; Dischino, Douglas D. (Bristol-Myers Squibb)Preparation of contrast agents for myocardial perfusion imagingcomprising an imaging moiety and deguelin, pyridaben, pyrimidifen,tebufenpyrad, fenazaquin, and analogs thereof. PCT Int. Appl. WO2005/079391. Sep. 1, 2005) in pyridine (2.00 mL) was cooled to 0° C.then treated with methyl chloroformate (34 μL, 0.44 mmol) in oneportion. After 1.25 h, additional methyl chloroformate (34 μL, 0.44mmol) was added. After an additional 1.5 h, a final addition of methylchloroformate (34 μL, 0.44 mmol) was performed. After 0.25 h, thesolution was diluted with ethyl acetate, with transfer to a separatoryfunnel, then washed with a 5% aqueous solution of CuSO₄, dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial thus obtained was then purified by chromatography on silica(30×175 mm) using 3:2 pentane/ethyl acetate. The main product peakeluting 175-280 mL was collected, pooled and concentrated in vacuo to acolorless oil (0.144 g, 0.339 mmol; 84.7%). ¹H NMR: (300 MHz, DMSO-d₆) δ8.26 (1H, s), 7.45 (2H, AB, J_(AB)=8.2 Hz), 7.37 (2H, AB, J_(AB)=8.4Hz), 5.45 (2H, s), 4.52 (2H, s), 4.29-4.19 (2H, m), 3.69 (3H, s),3.68-3.60 (2H, m), 1.57 (9H, s). ¹³C NMR: (75 MHz, DMSO-d₆) δ 157.8,155.2, 153.8, 138.6, 134.6, 127.8, 127.7, 126.2, 115.6, 71.5, 71.3,67.5, 66.7, 65.4, 54.6, 27.4. HRMS Calcd. for C₂₀H₂₅ ³⁵ClN₂O₆ (M+H):425.1474; found: 425.1470. TLC: R_(f) 0.50 (silica gel, 1:1pentane/ethyl acetate, CAM).

Example 38 Preparation of2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl2-cyanoacetate

A solution of 2-(tert-butyl)-4-chloro-5-((4-((2-hydroxyethoxy) methyl)benzyl) oxy) pyridazin-3(2H)-one⁶ (0.183 g, 0.500 mmol) and cyanoaceticacid (85.1 mg, 1.00 mmol) in dry dichloromethane (2.50 mL) was treatedwith N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.191g, 1.00 mmol) in one portion at ambient temperature. After 0.25 h, allvolatiles were removed in vacuo, and the residue directly purified bychromatography on silica (30×180 mm) using 1:1 pentane/ethyl acetate.The main product peak eluting 175-325 mL was collected, pooled andconcentrated in vacuo to a colorless oil (0.206 g, 0.476 mmol; 95.1%).¹H NMR: (300 MHz, CDCl₃) δ 7.72 (1H, s), 7.43-7.37 (4H, m), 5.31 (2H,s), 4.57 (2H, s), 4.41-4.38 (2H, m), 3.75-3.72 (2H, m), 3.49 (2H, s),1.63 (9H, s). ¹³C NMR: (75 MHz, CDCl₃) δ 162.9, 159.0, 153.6, 138.3,134.5, 128.2, 127.3, 125.0, 118.3, 112.8, 72.8, 71.6, 67.5, 66.4, 65.8,27.8, 24.7. HRMS Calcd. for C₂₁H₂₄ ³⁵ClN₃O₅ (M+H): 434.1477; found:434.1474. TLC: R_(f) 0.41 (silica gel, 1:1 pentane/ethyl acetate, uv).

Example 39 Preparation of2-(tert-butyl)-4-chloro-5-((6-(3-fluoropropoxy)pyridine-3-yl)methoxy)pyridazin-3(2H)-onePart A—Preparation of (6-(3-fluoropropoxy)pyridine-3-yl)methanol

A suspension of sodium hydride (26.4 mg, 1.10 mmol) and 3-fluoropropanol(78.0 mg, 1.00 mmol) in dimethylformamide (1.0 mL) was maintained atambient temperature for 25 min then treated with a solution of methyl6-bromonicotinate (0.216 g, 1.00 mmol) in dimethylformamide (0.5 mL).After 1 h, the resulting mixture was diluted with water (2 mL), theaqueous layer separated then extracted with ethyl acetate (2×10 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to a yellow oil.

A solution of methyl 6-(3-fluoropropoxy) nicotinate in tetrahydrofuranwas added dropwise to a cooled (0° C.) solution of lithium aluminumhydride (0.14 mL, 0.14 mmol, 1 M in tetrahydrofuran) and the resultingmixture warmed to ambient temperature. After 2 h, the solution wasdiluted with water, the aqueous layer separated then extracted withethyl acetate (3×10 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The crude material was thenpurified by silica gel chromatography (0-60% ethyl acetate in hexanes)to afford the desired product as a yellow oil (22.3 mg, 12.0% yield). ¹HNMR (CDCl₃, 300 MHz): δ 8.06-7.99 (m, 1H), 7.55 (dd, J=2.4, 8.4 Hz, 1H),6.66 (d, J=8.5 Hz, 1H), 4.63 (t, J=5.9 Hz, 1H), 4.54 (s, 2H), 4.47 (t,J=5.9 Hz, 1H), 4.30 (t, J=6.2 Hz, 2H), 2.18-2.01 (m, 2H). ¹³C NMR (75MHz, CDCl₃) δ 162.4, 144.7, 137.4, 128.1, 109.9, 79.9 (d, J_(CF)=165Hz), 61.4, 60.8, (d, J_(CF)=7.5 Hz), 29.2 (d, J_(CF)=22.5 Hz).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((6-(3-fluoropropoxy)pyridine-3-yl)methoxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (22.3 mg, 0.100mmol), the product of Example 39A (18.7 mg, 0.100 mmol), and cesiumcarbonate (52.5, 0.161 mmol) in dimethylformamide (1.0 mL) at ambienttemperature. Isolated yield—15.3 mg; 41.4%. ¹H NMR (CDCl₃, 300 MHz): δ8.12 (d, J=1.9 Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J=2.5, 8.5 Hz, 1H), 6.73(d, J=8.7 Hz, 1H), 5.15 (s, 2H), 4.64 (t, J=5.8 Hz, 1H), 4.48 (t, J=5.8Hz, 1H), 4.39 (t, J=6.2 Hz, 2H), 2.19-2.02 (m, 2H), 1.56 (s, 9H); ¹³CNMR (CDCl₃, 150 MHz): δ 163.1, 157.9, 152.4, 145.3, 137.5, 124.1, 122.3,117.7, 110.5, 79.8 (d, J_(CF)=165 Hz), 68.5, 65.4, 61.0 (d, J_(CF)=7.5Hz), 29.1 (d, J_(CF)=22.5 Hz), 26.8; HRMS Calcd. for C₁₇H₂₁³⁵ClFN₃O₅(M+H): 370.1328; found: 370.1331.

Example 40 Preparation of2-(tert-butyl)-5-((4-((2-fluoroethoxy)benzyl)oxy)-4-methylpyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-5-chloro-4-methylpyridrazin-3(2H)-one⁶ (0.100 g, 0.500mmol), (4-((2-fluoroethoxy)methyl)phenyl)methanol (0.110 g, 0.600 mmol),and cesium carbonate (0.261 g, 0.800 mmol) in dimethylformamide (5.0 mL)at 65° C. Isolated yield—49 mg; 28.1%. ¹H NMR (CDCl₃, 300 MHz): δ 7.61(s, 1H), 7.30 (br s, 4H), 5.10 (s, 2H), 4.59 (m, 1H), 4.53 (s, 2H), 4.43(m, 1H), 3.71 (m, 1H), 3.61 (m, 1H), 1.98 (s, 3H), 1.55 (s, 9H); ¹³C NMR(75 MHz, CDCl₃) δ 162.1, 153.3, 137.2, 134.3, 127.0, 126.2, 124.5,120.1, 82.0 (d, J_(CF)=165 Hz), 71.9, 69.8, 68.4 (d, J_(CF)=22.5 Hz),63.9, 27.0, 7.7; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₉H₂₅FN₂O₃:349.1922, found 349.1916.

Example 41 Preparation of2-((4-(((1-(tert-butyl)-5-methyl-6-oxo-1,6-dihydropyridazin-4yl)-oxy)methyl)benzyl)oxy)ethyl4-methylbenzenesulfonate Part A—Preparation of5-((4-(1,3-dioxolan-2-yl)benzyl)oxy)-2-(tert-butyl)-4-methylpyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-5-chloro-4-methylpyridrazin-3(2H)-one (0.200 g, 1.00mmol), (4-(1,3-dioxolan-2-yl)phenyl)methanol (0.150 g, 0.830 mmol), andcesium carbonate (0.540 g, 1.66 mmol) in dimethylformamide (10.0 mL) at60° C. Isolated yield—56.5 mg; 19.8%. ¹H NMR (CDCl₃, 300 MHz): δ 7.67(s, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 5.81 (s, 1H),5.20 (s, 2H), 4.26-3.84 (m, 4H), 2.05 (s, 3H), 1.57 (s, 9H); ¹³C NMR(CDCl₃, 75 MHz): δ 163.1, 154.3, 138.2, 136.8, 127.0, 126.9, 125.5,121.1, 103.3, 70.6, 65.3, 64.9, 28.0, 8.7; HRMS-TOF (m/z): [M+H]⁺ HRMS:Calcd. for C₁₉H₂₄N₂O₄: 345.1809, found 345.1806.

Part B—Preparation of2-(tert-butyl)-5-((4-((2-hydroxyethoxy)methyl)benzyl)oxy)-4-methylpyridazin-3(2H)-one

A solution of the product of Example 41A (55.7 mg, 0.162 mmol) intetrahydrofuran (0.8 mL) was added dropwise to a suspension of zirconiumchloride (37.8 mg, 0.162 mmol) and sodium borohydride (12.3 mg, 0.324mmol) in tetrahydrofuran (0.80 mL) at ambient temperature. After 2 h,the resulting mixture was diluted with water (5 mL), the aqueous layerseparated then extracted with ethyl acetate (3×10 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto a clear oil (50.6 mg, 90.2% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.62(s, 1H), 7.30 (br s, 4H), 5.10 (s, 2H), 4.50 (s, 2H), 3.70 (m, 2H), 3.54(dd, J=3.9, 5.3 Hz, 2H), 1.98 (s, 3H), 1.55 (s, 9H); ¹³C NMR (CDCl₃, 75MHz): δ 162.1, 153.4, 137.4, 134.3, 127.1, 126.8, 126.2, 119.3, 71.8,70.5, 69.8, 63.9, 60.8, 27.0, 7.7; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd.for C₁₉H₂₆N₂O₄: 347.1965, found 347.1960.

Part C—Preparation of2-((4-(((1-(tert-butyl)-5-methyl-6-oxo-1,6-dihydropyridazin-4yl)-oxy)methyl)benzyl)oxy)ethyl4-methylbenzenesulfonate

Prepared according to General Procedure D, using the product of Example41B (46.8 mg, 0.135 mmol), p-toluenesulfonyl chloride (30.9 mg, 0.162mmol), 4-dimethylaminopyridine (5.4 mg, 0.54 mmol), anddiisopropylethylamine (0.026 mL, 0.189 mmol). Isolated yield—42.6 mg;63.0%. ¹H (CDCl₃, 300 MHz): δ 7.80 (d, 2H, J=8.33 Hz), 7.69 (s, 1H),7.33 (m, 6H), 5.18 (s, 2H), 4.50 (s, 2H), 4.21 (m, 2H), 3.69 (m, 2H),2.43 (s, 3H), 2.05 (s, 3H), 1.63 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ163.1, 154.3, 144.7, 138.0, 135.3, 133.0, 129.7, 128.0, 127.9, 127.2,125.5, 121.2, 72.8, 70.8, 69.1, 67.7, 64.9, 28.0, 21.6, 8.7.

Example 43 Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-fluorobut-1-yn-1-yl)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of(4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)phenyl)methanol

A solution of methyl 4-(4-hydroxybut-1-yn-1-yl)benzoate (0.771 g, 3.77mmol),¹ in dimethylformamide (37.0 mL) was successively treated withtert-butylchlorodimethylsilane (0.848 g, 5.63 mmol), and imidazole(0.386 g, 5.67 mmol) at ambient temperature. After 2 h, the resultingmixture was diluted with water (150 mL), the aqueous layer separatedthen extracted with ethyl acetate (3×200 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated toyield to a yellow oil (1.50 g).

The crude silyl ether was dissolved in tetrahydrofuran (47.0 mL) thencooled to 0° C. and treated with lithium aluminum hydride (4.71 mL, 4.71mmol, 1 M in tetrahydrofuran). The resulting solution then warmed slowlyto ambient temperature and, after 2 h, was diluted with water (20 mL).The aqueous layer was separated then extracted with ethyl acetate (3×50mL) and the combined organic layers washed with saturated aqueous sodiumchloride, dried over sodium sulfate, filtered, and concentrated in vacuo(1.22 g, >98% crude yield). ¹H (CDCl₃, 300 MHz): δ 7.29 (d, J=8.28 Hz,2H), 7.18 (d, J=8.47 Hz, 2H), 4.58 (s, 2H), 3.72 (t, J=7.05 Hz, 2H),2.53 (t, J=7.03 Hz, 2H), 0.82 (s, 6H); 0.01 (s, 9H); HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₇H₂₆O₂Si: 291.1775, found 291.1763.

Part B—Preparation of2-(tert-butyl)-5-((4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)benzyl)oxy)-4-chloropyridazinone-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.318 g, 1.45 mmol),the product of Example 43A (0.500 g, 1.73 mmol), and cesium carbonate(0.750 g, 2.31 mmol) in dimethylformamide (14.5 mL) at 60° C. Isolatedyield—0.242 g; 35.1%. ¹H NMR (CDCl₃, 300 MHz): δ 5 7.58 (s, 1H), 7.33(d, J=8.3 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 5.19 (s, 2H), 3.72 (t, J=7.0Hz, 2H), 2.53 (t, J=6.9 Hz, 2H), 1.44 (s, 9H), 0.82 (s, 9H), 0.20 (s,6H); ¹³C NMR (CDCl₃, 75 MHz, partial): δ 159.0, 153.5, 134.2, 132.1,127.1, 126.8, 125.1, 124.4, 118.4, 88.3, 80.9, 71.5, 66.4, 61.8, 27.8,25.8, 23.8, −5.2; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₅H₃₅³⁵ClN₂O₃Si: 475.2178, found 475.2162.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)pyridazinone-3(2H)-one

A solution of the product of Example 43B (0.242 g, 0.510 mmol) dissolvedin tetrahydrofuran (10.0 mL) was treated with a solution oftetrabutylammonium fluoride (1.02 mL, 1.02 mmol, 1 M in tetrahydrofuran)at ambient temperature. After 2 h, the resulting mixture wasconcentrated in vacuo and the residue directly purified by silica gelchromatography (0-60% ethyl acetate in hexanes) to afford the desiredproduct as an oil (0.120 g, 65.2% yield). ¹H NMR (CDCl₃, 300 MHz): δ7.68 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.29 (s,2H), 3.82 (m, 4H), 1.63 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 158.9,153.5, 134.5, 132.2, 126.9, 125.0, 123.9, 118.4, 87.4, 81.8, 71.4, 66.4,61.1, 27.8, 23.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for Cl₉H₂₁³⁵ClN₂O₃: 361.1313, found 361.1309.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-fluorobut-1-yn-1-yl)benzyl)oxy)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 43C (0.050 g, 0.138mmol) in dichloromethane (0.10 mL) was treated with Deoxofluor (0.152mmol, 33.7 mg, 50% in toluene) then maintained 1.5 h. The resultingmixture was diluted with water (1 mL), the aqueous layer separated thenextracted with dichloromethane (3×2 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was then purified by preparative thin layerchromatography on silica using 3:2 hexanes/ethyl acetate to afford thedesired product (11.5 mg, 23.0% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.61(s, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.22 (s, 2H),4.59 (t, J=6.6 Hz, 1H), 4.44 (t, J=6.6 Hz, 1H), 2.78 (dt, J=19.6, 6.6Hz, 2H), 1.56 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 157.9, 152.5, 133.6,131.2, 125.8, 124.0, 122.8, 117.4, 84.4 (d, J_(CF)=15 Hz), 80.3 (d,J_(CF)=165 Hz), 80.6, 70.4, 65.4, 26.8, 20.6 (d, J_(CF)=22.5 Hz);HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C ₁₉H₂₀ ³⁵ClFN₂O₂: 363.1270,found 363.1270.

Example 44 Preparation of4-(4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)-oxy)methyl)benzyl)but-3-yn-1-yl4-methylbenzenesulfonate

Prepared according to General Method D, using the product of Example 43C(77.4 mg, 0.215 mmol), p-toluenesulfonyl chloride (49.2 mg, 0.258 mmol),4-dimethylaminopyridine (1.1 mg, 0.0086 mmol), and triethylamine (0.042mL, 0.30 mmol). Isolated yield—42.2 mg; 38.1%. ¹H (CDCl₃, 300 MHz): δ7.75 (d, J=8.3 Hz, 2H), 7.61 (s, 1H), 7.36-7.21 (m, 6H), 5.22 (s, 2H),4.12 (t, J=6.9 Hz, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.35 (s, 3H), 1.56 (s,9H); ¹³C (CDCl₃, 75 MHz): δ 158.9, 153.5, 144.9, 134.7, 132.9, 132.1,129.8, 127.9, 126.8, 125.0, 123.5, 118.4, 84.8, 82.0, 71.4, 67.6, 66.4,27.8, 21.6, 20.4; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₂₆H₂₇³⁵ClN₂O₆S: 515.1402, found 515.1409.

Example 45 Preparation of 2-fluoroethyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

A suspension of 2-fluoroethanol (2 mL) and potassium tert-butoxide(0.0300 g, 0.267 mmol) was heated to 60° C., maintained 20 min thentreated with a solution of methyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate(93.5 mg, 0.267 mmol)⁴ in tetrahydrofuran (0.70 mL). The resultingmixture was stirred overnight then cooled to ambient temperature anddiluted with water (5 mL). The aqueous layer was separated, extractedwith ethyl acetate (3×20 mL), and the combined organic layers washedwith saturated aqueous sodium chloride, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was thenpurified by silica gel chromatography (0-80% diethyl ether in hexanes)to afford the desired product as a white solid (11.7 mg, 11.4% yield).¹H (CDCl₃, 300 MHz): δ 8.17-8.08 (m, 2H), 7.70 (s, 1H), 7.51 (d, J=8.0Hz, 2H), 5.38 (s, 2H), 4.81 (m, 1H), 4.61-4.67 (m, 2H), 4.53 (m, 1H),1.63 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 164.7, 157.9, 152.3, 139.1,129.4, 129.0, 125.7, 123.8, 117.5, 80.2 (d, J_(CF)=165 Hz), 70.1, 65.4(d, J_(CF)=22.5 Hz), 62.8, 20.0.

Example 46 Preparation of 2-(tosyloxy)ethyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoatePart A—Preparation of 2-hydroxyethyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

A suspension of ethylene glycol (15 mL) and potassium tert-butoxide(0.224 g, 2.00 mmol) was heated to 60° C., maintained 20 min thentreated with a solution of methyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate(0.773 g, 2.20 mmol) in tetrahydrofuran (5.0 mL). After 1.5 h, theresulting mixture was cooled to ambient temperature and diluted withwater (50 mL). The aqueous layer was separated then extracted withtoluene (3×100 mL), and the combined organic layers were washed withsaturated aqueous sodium chloride, dried over sodium sulfate, filtered,and concentrated. The crude material was then purified by silica gelchromatography (40-60% ethyl acetate in hexanes) to afford the desiredproduct as a white solid (47.7 mg, 5.3% yield). ¹H (CDCl₃, 300 MHz): δ8.11 (d, J=8.4 Hz, 2H), 7.71 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 5.37 (s,2H), 4.59-4.34 (m, 2H), 4.04-3.86 (m, 2H), 1.63 (s, 9H); HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₈H₂₁ ³⁵ClN₂O₅: 381.1212, found 384.1206.

Part B—Preparation of 2-(tosyloxy) ethyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

Prepared according the General Method D, using the product of Example46A (47.1 mg, 0.124 mmol), p-toluenesulfonyl chloride (28.3 mg, 0.148mmol), 4-dimethylaminopyridine (0.60 mg, 0.0049 mmol), and triethylamine(0.024 mL, 1.4 mmol). Isolated yield—33.6 mg; 50.6%. ¹H (CDCl₃, 300MHz): δ 8.07-7.96 (m, 2H), 7.78 (s, 1H), 7.71 (m, 2H), 7.49 (d, J=8.3Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.37 (s, 2H), 4.54-4.46 (m, 2H),4.41-4.32 (m, 2H), 2.40 (s, 3H), 1.64 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz):δ 165.4, 158.9, 153.4, 145.0, 140.2, 132.8, 130.4, 129.9, 129.7, 127.9,127.5, 126.7, 118.5, 71.0, 67.5, 66.6, 62.2, 27.8, 21.6; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₂₅H₂₇ ³⁵CN₂O₇S: 535.1300, found 535.1290.

Example 47 Preparation of2-(tert-butyl)-4-chloro-5-((4′-(3-fluoropropoxy)-[1,1′-biphenyl]-4-yl)methoxy)pyridazin-3(2H)-onePart A—Preparation of4′-(3-fluoropropoxy)-[1,1′-biphenyl]-4-carbaldehyde

Prepared according to General Method F, using4′-hydroxy-[1,1′biphenyl]-4-carbaldehyde (0.500 g, 2.52 mmol),3-fluoropropyl p-toluenesulfonate (0.557 g, 2.40 mmol), and cesiumcarbonate (1.25 g, 3.84 mmol) in dimethylformamide (25.2 mL) was atambient temperature. The crude material was further purified by silicagel chromatography (0-60% ethyl acetate in hexanes) to afford thedesired product as a white solid (0.380 g, 61.3% yield). ¹H NMR (CDCl₃,300 MHz): δ 10.03 (s, 1H), 7.97-7.87 (m, 2H), 7.75-7.68 (m, 2H),7.63-7.53 (m, 2H), 7.06-6.96 (m, 2H), 4.75 (t, J=5.7 Hz, 1H), 4.59 (t,J=5.7 Hz, 1H), 4.16 (t, J=6.1 Hz, 2H), 2.21 (m, 2H); ¹³C NMR (CDCl₃, 75MHz, CDCl₃) δ 191.8, 159.3, 146.7, 134.7, 132.2, 130.2, 128.5, 127.0,115.0, 80.6 (d, J_(CF)=165 Hz), 63.7 (d, J_(CF)=7.5 Hz), 30.4 (d,J_(CF)=22.5 Hz); HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₆H₁₅FO₂:259.1129, found 259.1131.

Part B—Preparation of 4′-(3-fluoropropoxy)-[1,1′-biphenyl]-4-yl)methanol

A cooled (0° C.) solution of the product of Example 47A (0.190 g, 0.730mmol) dissolved in tetrahydrofuran (7.3 mL) was treated with a solutionof lithium aluminum hydride (0.40 mL, 0.40 mmol, 1 M in tetrahydrofuran)then warmed to ambient temperature. After 2 h, the resulting mixture wasdiluted with water (10 mL), the aqueous layer separated then extractedwith ethyl acetate (3×50 mL). The combined organic layers were driedover sodium sulfate and concentrated to a white solid (0.170 g, 89.5%yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.60-7.47 (m, 4H), 7.42 (d, J=8.4 Hz,2H), 7.03-6.88 (m, 2H), 4.83-4.63 (m, 3H), 4.59 (t, J=5.7 Hz, 1H), 4.15(t, J=6.1 Hz, 2H), 2.20 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 158.3, 140.2,139.2, 133.5, 128.1, 127.4, 126.8, 114.8, 80.7 (d, J_(CF)=165 Hz), 65.1,63.7 (d, J_(CF)=7.5 Hz), 30.4 (d, J_(CF)=22.5 Hz); HRMS-TOF (m/z):[M+Na]⁺ HRMS: Calcd. for C₁₆H₁₇FO₂: 261.1285, found 261.1282.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4′-(3-fluoropropoxy)-[1,1′-biphenyl]-4-yl)methoxy)pyridazin-3(2H)-one

Prepared according to General Procedure B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.120 g, 0.540 mmol),the product of Example 47B (0.170 g, 0.650 mmol), and cesium carbonate(0.265 g, 0.816 mmol) in dimethylformamide (6.5 mL) at 65° C. Isolatedyield—12.7 mg; 5.3%. ¹H NMR (CDCl₃, 300 MHz): δ 7.53 (s, 1H), 7.49-7.38(m, 6H), 6.94-6.85 (m, 2H), 5.53 (s, 2H), 4.67 (t, J=5.7 Hz, 1H), 4.51(t, J=5.7 Hz, 1H), 4.07 (t, J=6.1 Hz, 2H), 2.12 (m, 2H), 1.57 (s, 9H);¹³C NMR (CDCl₃, 75 MHz): δ 160.7, 158.4, 150.5, 140.8, 134.9, 133.3,129.0, 128.1, 126.6, 124.5, 114.8, 80.7 (d, J_(CF)=165 Hz), 73.4, 65.7,63.6 (d, J_(CF)=22.5 Hz), 30.5 (d, J_(CF)=7.5 Hz), 27.8; HRMS-TOF (m/z):[M+Na]⁺ HRMS: Calcd. for C₂₄H₂₆ ³⁵ClFN₂O₃: 445.1689, found 445.1684.

Example 48 Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-fluoropyrimidin-5-yl)-benzyl)oxy)pyridazin-3(2H)one Part A—Preparation of 2-(tert-butyl)-4-chloro-5-((4-(4, 4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.537 g, 2.65 mmol) in tetrahydrofuran (22.1 mL) was successivelytreated with(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.745g, 3.18 mmol), triphenylphosphine (1.04 g, 3.97 mmol), anddiisopropylazodicarboxylate (0.782 mL, 3.97 mmol) at ambienttemperature. After 45 min, the resulting mixture was diluted with water(20 mL), the aqueous layer separated then extracted with ethyl acetate(3×50 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was suspended indiethyl ether, stirred 3 h then collected by filtration and purified bysilica gel chromatography using 4:1 hexane/ethyl acetate to afford thedesired product as a white solid (0.347 g, 31.3% yield). ¹H NMR (300MHz, DMSO-d₆): δ 8.22 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0Hz, 2H), 5.49 (s, 2H), 1.57 (s, 9H), 1.30 (s, 12H); ¹³C NMR (75 MHz,DMSO-d₆, partial): δ 157.7, 153.5, 138.6, 134.7, 126.9, 125.1, 115.6,83.7, 71.1, 65.3, 27.4, 24.6; HRMS-TOF (m/z): [M+Na]⁺ HRMS: Calcd. forC₂₁H₂₈B³⁵ClN₂O₄: 419.1907, found 419.1903.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-chloropyrimidin-5-yl)benzyl)oxy)pyridazin-3(2H)-one

2-Chloro-5-bromopyrimidine (41.3 mg, 0.215 mmol) andtetrakis(triphenylphosphine) palladium (0) (7.0 mg, 2.5 mol %) weredissolved in 1,2-dimethoxyethane (1.0 mL) at ambient temperature,maintained 15 min then successively treated with the product of Example48A (0.090 g, 0.215 mmol) as a solution in 1,2-dimethoxyethane (1.2 mL)and aqueous potassium carbonate (0.43 mL, 0.43 mmol). The resultingmixture was warmed to 80° C., maintained 1.5 h then cooled to ambienttemperature and diluted with water (2 mL). The aqueous layer wasseparated then extracted with ethyl acetate (3×10 mL), and the combinedorganic layers dried over sodium sulfate, filtered and concentrated to alight yellow solid (59.0 mg, 67.7% yield). ¹H NMR (DMSO-d₆, 300 MHz): δ9.26 (s, 2H), 8.40 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz,2H), 5.65 (s, 2H), 1.69 (s, 9H); ¹³C NMR (75 MHz, DMSO-d₆): δ 159.0,158.0, 157.7, 153.7, 136.5, 132.6, 131.7, 128.5, 127.3, 126.1, 115.7,70.9, 65.4, 27.5

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-fluoropyrimidin-5-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 48B (97.0 mg, 0.024 mmol), indimethyl sulfoxide (0.25 mL) was treated with potassium fluoride (1.43mg, 0.024 mmol) and Kryptofix™ (18 mg, 0.48 mmol) then heated to 80° C.and maintained 10 min. The resulting mixture was cooled to ambienttemperature then diluted with 1 mL of dichloromethane and directlypurified by preparative thin layer chromatography on silica using 4:1hexanes/ethyl acetate to afford the desired product as a white solid(1.3 mg, 13.9% yield). ¹H NMR (DMSO-d₆, 600 MHz): δ 9.22 (d, J=1.6 Hz,2H), 8.35 (s, 1H), 7.96-7.90 (m, 2H), 7.69 (d, J=8.3 Hz, 2H), 5.81 (s,2H), 1.64 (s, 9H); ¹³C NMR (DMSO-d₆, 150 MHz, partial): δ 159.3 (d,J_(C)=15 Hz), 136.2, 129.5, 128.5, 127.2, 126.1, 71.0, 65.4, 27.4; ¹⁹FNMR (DMSO-d₆, 262 MHz): δ −49.19 (br s, 1H).

Example 49 Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-(fluoromethyl)phenyl)but-3-yn-1-yl)oxy)pyridazin-3(2H)-onePart A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-hydroxymethyl)phenyl)but-3-yn-1-yl)oxy)pyridazin-3(2H)-one

2-(tert-Butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one (62.0 mg, 0.368mmol), triphenylphosphine (0.145 g, 0.552 mmol) and methyl4-(4-hydroxybut-1-yn-1-yl) benzoate (74.4 mg, 0.442 mmol)¹ were combinedin dry tetrahydrofuran (3.7 mL), then cooled to 0° C. and treated withdiethyl azodicarboxylate (0.109 mL, 0.552 mmol). The resulting mixturewarmed slowly to ambient temperature, and after 1.5 h was diluted withwater (10 mL). The aqueous layer was separated then extracted with ethylacetate (3×20 mL), and the combined organic layers dried over sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by silica gel chromatography (0-80% ethyl acetate in hexanes)to afford the desired product (40 mg).

A cooled (0° C.) solution of the ester (40.0 mg, 0.103 mmol) intetrahydrofuran (1.0 mL) was treated with a solution of lithium aluminumhydride (0.05 mL, 0.05 mmol, 1 M in tetrahydrofuran) then warmed toambient temperature. After 2 h, the resulting mixture was diluted withwater (2 mL), the aqueous layer separated then extracted with ethylacetate (3×5 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by silica gel chromatography (0-20% ethyl acetate in hexanes)to afford the desired product (31.5 mg, 23.7% yield). ¹H NMR (CDCl₃, 300MHz): δ 7.72 (s, 1H), 7.33-7.28 (m, 2H), 7.24-7.18 (m, 2H), 4.61 (s,2H), 4.35 (t, J=6.8 Hz, 2H), 2.89 (t, J=6.88 Hz, 2H); 1.57 (s, 9H); ¹³CNMR (CDCl₃, 75 MHz): δ 159.0, 153.6, 141.0, 131.7, 126.7, 125.1, 122.0,118.3, 84.2, 82.8, 68.4, 66.4, 64.8, 27.8, 20.8; HRMS-TOF (m/z): [M+H]⁺HRMS: Calcd. for C₁₉H₂₁ ³⁵ClN₂O₃: 361.1313, found 361.1315.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-(fluoromethyl)phenyl)but-3-yn-1-yl)oxy)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 49A (31.8 mg, 0.088mmol) in dichloromethane (1.0 mL) was treated with Deoxofluor (21.3 mg,0.096 mmol; 50% in toluene) and maintained 1.5 h. The resulting mixturewas diluted with water (1 mL), the aqueous layer separated thenextracted with dichloromethane (3×2 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was then purified by preparative thin layerchromatography on silica using 4:1 hexanes/ethyl acetate to afford thedesired product (11.5 mg, 36.0% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.71(s, 1H), 7.37-7.29 (m, 2H), 7.26-7.19 (m, 2H), 5.37 (s, 1H), 5.21 (s,1H), 4.35 (t, J=6.8 Hz, 2H), 2.90 (t, J=6.8 Hz, 2H), 1.57 (s, 9H); ¹³CNMR (CDCl₃, 75 MHz): δ 159.0, 153.6, 136.2 (d, J_(CF)=22.5 Hz), 131.8,127.2 (d, J_(CF)=7.5 Hz), 125.1, 123.3, 118.3, 84.0 (d, J_(CF)=165 Hz),84.8, 82.5, 68.3, 66.4, 27.8, 20.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd.for C₁₉H₂₀ ³⁵ClFN₂O₃: 363.1270, found 363.1268.

Example 50 Preparation of2-(tert-butyl)-4-chloro-5-((2,3,5-dichloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of (2,3,5-dichloro-4-(3-fluoropropoxy)phenyl)methanol

Prepared according to General Method F, using2,3,5-dichloro-4-hydroxymethylbenzoate (1.00 g, 4.52 mmol),3-fluoropropyl p-toluenesulfonate (1.26 g, 5.42 mmol), and cesiumcarbonate (2.35 g, 7.23 mmol) in dimethylformamide (45.0 mL) at 65° C.Isolated yield—0.650 g; 50.4%.

A solution of the crude ester (63.0 mg, 0.200 mmol) dissolved in ethanol(2.0 mL) was treated with sodium borohydride (5.7 mg, 0.15 mmol) in oneportion at ambient temperature. The resulting mixture was stirred 2 dthen diluted with water (20 mL) and concentrated in vacuo to remove theethanol. The resulting aqueous solution was extracted with ethyl acetate(3×100 mL) and the combined organic layers dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was purified bysilica gel chromatography using 4:1 hexanes/ethyl acetate to afford thedesired product (52.7 mg, 91.6% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.42(s, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.66 (s, 2H), 4.59 (t, J=5.8 Hz, 1H),4.07 (t, J=6.0 Hz, 2H), 2.16 (m, 2H); ¹³C NMR (CDCl₃, 150 MHz): δ 151.3,136.3, 129.8, 129.0, 127.7, 127.0, 80.6 (d, J_(C)=165 Hz), 69.3 (d,J_(CF)=7.5 Hz), 62.3, 31.1 (d, J_(CF)=22.5 Hz).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((2,3,5-dichloro-4-(3-fluoropropoxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (39.2 mg, 0.178 mmol),the product of Example 50A (61.2 mg, 0.213 mmol), and cesium carbonate(92.5 mg, 0.284 mmol) in dimethylformamide (1.7 mL) at 65° C. Isolatedyield—23.0 mg; 27.4%. ¹H NMR (CDCl₃, 300 MHz): δ 7.89-7.68 (br s, 1H),7.67-7.41 (br s, 1H), 5.32 (s, 2H), 4.93-4.74 (m, 1H), 4.75-4.54 (m,1H), 4.19 (m, 2H), 2.41-2.11 (m, 2H), 1.56 (s, 9H); ³C NMR (CDCl₃, 75MHz) δ 158.8, 153.1, 152.5, 130.7, 130.0, 129.6, 128.2, 127.4, 124.7,118.7, 80.4 (d, J_(CF)=165 Hz), 69.4 (d, J_(CF)=7.5 Hz), 68.6, 66.6,31.1 (d, J_(CF)=22.5 Hz), 27.8; HRMS: Calcd. for C₁₈H₁₉ ³⁵Cl₄FN₂O₃:471.0207, found 471.0206.

Example 51 Preparation of2-(tert-butyl)-4-chloro-5-(4-((2-fluoroethoxy)methyl)phenyl)pyridazin-3(2H)-onePart A—Preparation of5-((4-(1,3-dioxolan-2-yl)phenyl)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

A cooled (0° C.) solution of2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (3.00 g, 13.6 mmol) indiethyl ether (6.5 mL) was treated with(4-(1,3-dioxolan)-2-yl)phenyl)magnesium bromide solution (27.3 mL, 13.6mmol, 0.5 M in tetrahydrofuran) and maintained 30 min. The resultingmixture was diluted with water (20 mL), the aqueous layer separated thenextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by silica gel purification (0-30% ethylacetate in hexanes) to afford the desired product as a white solid (2.87g, 63.0% yield). ¹H NMR (CDCl₃, 300 MHz) δ 7.81 (s, 1H), 7.59 (d, J=8.1Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 5.91 (s, 1H), 4.25-3.94 (m, 4H), 1.68(s, 9H).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-hydroxyethoxy)methyl)phenyl)pyridazin-3(2H)-one

A solution of the product of Example 51A (0.342 g, 1.02 mmol) intetrahydrofuran (2.0 mL) was added dropwise to a suspension of zirconiumchloride (0.238 g, 1.02 mmol) and sodium borohydride (77.3 mg, 2.04mmol) in tetrahydrofuran (3.1 mL) at ambient temperature. After 3 h, theresulting mixture was diluted with water (10 mL), the aqueous layerseparated then extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto a clear oil (0.322 g, 93.7% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.72(s, 1H), 7.36 (br s, 4H), 4.54 (s, 2H), 3.70 (m, 2H), 3.56 (m, 2H), 1.59(s, 9H); ¹³C NMR (CDCl₃, 75 MHz): 159.6, 153.2, 139.0, 135.1, 134.9,131.0, 129.8, 127.2, 72.9, 71.4, 66.0, 61.9, 27.8; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₇H₂₁ ³⁵ClFN₂O₃: 337.1313, found 337.1311.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-(4-((2-fluoroethoxy)methyl)phenyl)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 51B (0.100 g, 0.297mmol) in dichloromethane (3.0 mL) was treated with Deoxofluor (72.3 mg,0.326 mmol; 50% in toluene) and maintained 2 h. The resulting mixturewas diluted with water (10 mL), the aqueous layer separated thenextracted with dichloromethane (3×10 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was then purified by preparative thin layerchromatography on silica using 4:1 hexanes/ethyl acetate to afford thedesired product as a white solid (19.7 mg, 19.6% yield). ¹H NMR (CDCl₃,300 MHz): δ 7.72 (s, 1H), 7.36 (s, 4H), 4.60 (m, 1H), 4.57 (s, 2H),4.46-4.39 (m, 1H), 3.75-3.68 (m, 1H), 3.65-3.58 (m, 1H), 1.58 (s, 9H);¹³C NMR (CDCl₃, 75 MHz): δ 159.6, 153.1, 138.8, 135.1, 134.9, 131.0,129.8, 127.2, 83.0 (d, J_(CF)=165 Hz), 72.9, 69.2 (d, J_(CF)=22.5 Hz),66.0, 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS: Calcd. for C₁₇H₂₀ ³⁵ClFN₂O₂:339.1270, found 339.1268.

Example 52 Preparation of2-(tert-butyl)-4-chloro-5-(4-(3-fluoropropyl)phenoxy)pyridazin-3(2H)-onePart A—Preparation of methyl3-(4-((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)phenyl)propanoate

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.750 g, 3.39 mmol),methyl 3-(4-hydroxyphenyl)propionate (0.734 g, 4.07 mmol), and cesiumcarbonate (1.76 g, 5.43 mmol) in dimethylformamide (34.0 mL) at roomtemperature overnight. Isolated yield—0.960 g; 77.6%. ¹H NMR (CDCl₃, 300MHz): δ 7.40 (s, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.05-6.99 (m, 2H), 3.68(s, 3H), 2.97 (m, 2H), 2.64 (m, 2H), 1.64 (s, 9H); ¹³C NMR (CDCl₃, 75MHz) δ 172.9, 158.9, 152.9, 152.2, 138.2, 130.1, 127.0, 120.2, 119.8,66.4, 51.6, 35.5, 30.1, 27.8; HRMS: Calcd. for C₁₈H₂₁ ³⁵ClN₂O₄:365.1263, found 365.1259.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-(4-(3-hydroxypropyl)phenoxy)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 52A (0.473 g, 1.30mmol) in tetrahydrofuran (13 mL) was treated with lithium aluminumhydride (0.65 mL, 0.65 mmol, 1 M in tetrahydrofuran) then warmed toambient temperature. After 1 h, the resulting mixture was diluted withwater (10 mL), the aqueous layer separated then extracted with ethylacetate (3×50 mL). The combined organic layers were washed withsaturated aqueous sodium chloride, dried over sodium sulfate, filtered,and concentrated to a light yellow solid (0.384 g, 87.7%). ¹H (CDCl₃,600 MHz): δ 7.40 (s, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.05-6.98 (m, 2H),3.75-3.65 (m, 2H), 2.79-2.68 (m, 2H), 1.97-1.82 (m, 2H), 1.65 (s, 9H);³C NMR (CDCl₃, 150 MHz) δ 158.9, 153.0, 151.9, 139.6, 130.1, 127.0,120.0, 119.7, 66.4, 61.9, 34.1, 31.3, 27.8; HRMS-TOF (m/z): [M+H]⁺ HRMS:Calcd. for C₁₇H₂₁ ³⁵ClN₂O₃: 337.1313, found 337.1319.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-(4-(3-fluoropropyl)phenoxy)pyridazin-3(2H)-one

A cooled (0° C.) solution of the product of Example 52B (50.0 mg, 0.149mmol) in dichloromethane (0.1 mL) was treated with Deoxofluor (36.0 mg,0.164 mmol; 50% in toluene) and maintained 1.5 h. The resulting mixturewas diluted with water (1 mL), the aqueous layer separated thenextracted with dichloromethane (2×10 mL). The combined organic portionswere dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was then purified by silica gel chromatography (0-50%ethyl acetate in hexanes) to afford the desired product as a yellow oil(5.6 mg, 11.1% yield). ¹H NMR (CDCl₃, 600 MHz, contains small amount ofalcohol starting material): δ 7.34 (s, 1H), 7.18 (d, J=8.0 Hz, 2H), 6.96(m, 2H), 4.48 (t, J=5.8 Hz, 1H), 4.32 (t, J=5.8 Hz, 1H), 3.47 (t, J=6.3Hz, 2H), 2.02 (m, 2H), 1.58 (s, 9H); ¹³C NMR (CDCl₃, 150 MHz, containssmall amount of alcohol starting material): δ 157.9, 151.9, 151.1,137.8, 129.3 (129.2), 126.0, 118.8, 81.8 (d, J_(CF)=165 Hz), 65.4, 42.9,31.1 (d, J_(C)=22.5 Hz), 29.7 (d, J_(C)=7.5 Hz), 26.84; HRMS-TOF (m/z):[M+H]⁺ HRMS: Calcd. for C₁₇H₂₀ ³⁵ClFN₂O₂: 339.1270, found 339.1268.

Example 53 Preparation of2-(tert-butyl)-4-chloro-5-((2-fluoropyridin-3-yl)oxy)pyridazin-3(2H)-onePart A—Preparation of2-(tert-butyl)-4-chloro-5-((2-nitropyridin-3-yl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4,5-dichloropyridrazin-3(2H)-one (0.221 g, 1.00 mmol),2-nitropyridin-3-ol (0.140 g, 1.00 mmol), and cesium carbonate (0.170 g,0.52 mmol) in dimethylformamide (2.0 mL) at 80° C. Isolated yield—0.120g; 37.0%. ¹H NMR (300 MHz, DMSO-d₆): δ 8.52 (dd, J=4.5, 1.3 Hz, 1H),8.22 (dd, J=8.4, 1.3 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J=8.4, 4.5 Hz,1H), 1.60 (s, 9H); ¹³C NMR (75 MHz, DMSO-d₆): δ 157.62, 151.15, 144.95,142.38, 138.09, 132.05, 130.95, 128.14, 121.01, 65.99, 27.33. HRMSCalcd. for C₁₃H₁₃ ³⁵ClN₄O₄(M+H): 325.0698; found: 325.0697.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((2-fluoropyridin-3-yl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 53A (35.7 mg, 0.110 mmol),potassium fluoride (9.0 mg, 0.15 mmol), and Kryptofix™ (60.2 mg, 0.16mmol) in dimethylsulfoxide (2.5 mL) was heated to 125° C. and maintained30 min. The resulting mixture was then cooled to ambient temperature anddiluted with ethyl acetate (40 mL). The organic layer was separated thenwashed with water (2×50 mL) and saturated aqueous sodium chloride, driedover magnesium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by silica gel chromatography (10-40% ethylacetate in hexanes) to afford the desired product as colorless oil (25.0mg, 76.3% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.14 (dt, J=4.8, 1.6 Hz,1H), 8.00 (ddd, J=10.2, 7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.45 (ddd,J=7.9, 4.8, 0.9 Hz, 1H), 1.60 (s, 9H); ¹³C NMR (75 MHz, DMSO-d₆): δ157.63, 151.52, 143.31 (d, J_(CF)=13.5 Hz), 136.40, 136.04, 131.60 (d,J_(C)=3.0 Hz), 127.70, 123.54 (d, J_(CF)=4.5 Hz), 120.18, 65.94, 27.34;¹⁹F NMR (282 MHz, DMSO-d₆): δ −83.96 (d, J=10.2 Hz). HRMS Calcd. forC₁₃H₁₃ ³⁵ClFN₃O₂(M+H): 298.0753; found: 298.0753.

Example 54 Preparation of2-(tert-butyl)-4-chloro-5-((4-(6-nitropyridin-3-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 5-bromo-2-nitropyridine (50.7 mg, 0.250 mmol) and tetrakis(triphenylphosphine) palladium (0) (6.7 mg; 2.3 mol %) indimethoxyethane (1.5 mL), was successively treated with the product ofExample 48A (0.105 g, 0.250 mmol) as a solution in 1.5 mLdimethoxyethane, and aqueous potassium carbonate (0.50 mmol; 0.50 mL) atambient temperature. The resulting mixture was heated to 80° C.,maintained 2 h then cooled back to ambient temperature and diluted withethyl acetate (50 mL). The organic layer was separated, washed withwater (2×50 mL) and saturated aqueous sodium chloride then dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by silica gel chromatography (20-50% ethylacetate in hexanes) to afford the desired product as a faint yellowsolid (75.0 mg, 72.3% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.46 (dd,J=2.7, 0.7 Hz, 1H), 8.68 (dd, J=8.8, 2.7 Hz, 1H), 8.36-8.23 (m, 4H),7.71-7.61 (m, 2H), 5.57 (s, 2H), 1.58 (s, 9H); ¹³C NMR (75 MHz,DMSO-d₆): δ 160.45, 157.79, 153.78, 144.87, 143.15, 138.17, 136.64,132.71, 128.22, 127.89, 126.17, 120.68, 115.73, 70.90, 65.43, 27.46.HRMS Calcd. for C₂₀H₁₉ ³⁵ClN₄O₄ (M+H): 415.1168; found: 415.1168.

Example 55 Preparation of2-(tert-butyl)-4-chloro-5-((4-(6-fluoropyridin-3-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 5-bromo-2-fluoropyridine (37.0 mg, 0.210 mmol) andtetrakis (triphenyl-phosphine) palladium (0) (9.0 mg; 3.9 mol %) indimethoxyethane (1.0 mL) was successively treated with the product ofExample 48A (85.0 mg, 0.200 mmol) as a solution in 1.0 mLdimethoxyethane, and aqueous potassium carbonate (0.50 mmol; 0.50 mL) atambient temperature. The resulting mixture was heated to 80° C.,maintained 2 h then cooled back to ambient temperature and diluted withethyl acetate (50 mL). The organic layer was separated, washed withwater (2×50 mL) and saturated aqueous sodium chloride then dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by silica gel chromatography (20-50% ethylacetate in hexanes) to afford the desired product as white solid (50.0mg, 64.5% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.58 (dt, J=2.6, 0.8 Hz,1H), 8.38-8.24 (m, 2H), 7.87-7.74 (m, 2H), 7.65-7.54 (m, 2H), 7.30 (ddd,J=8.6, 2.9, 0.7 Hz, 1H), 5.52 (s, 2H), 1.58 (s, 9H); ¹³C NMR (75 MHz,DMSO-d₆) δ 157.79, 153.82, 145.45 (d, J_(CF)=15.0 Hz), 140.34 (d,J_(CF)=8.3 Hz), 136.01, 135.39, 133.62 (d, J_(CF)=4.5 Hz), 128.52,127.17, 126.18, 115.67, 109.89, 109.39, 71.03, 65.40, 27.47; ¹⁹F NMR(282 MHz, DMSO-d₆): δ −70.87 (dd, J=8.0, 2.8 Hz). HRMS Calcd. for C₂₀H₁₉³⁵ClFN₃O₂(M+H): 388.1223; found: 388.1217.

Example 56 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoropyridin-3-yl)oxy)benzyl)oxy)pyridazin-3(2H)-onePart A—Preparation of 2-nitro-3-(p-tolyoxy)pyridine

A suspension of p-cresol (0.325 g, 3.00 mmol), 3-bromo-2-nitropyridine(0.404 g, 2.00 mmol), and potassium carbonate (0.345 g, 2.50 mmol) inacetonitrile (2.0 mL) was heated at 70° C. and maintained 16 h. Theresulting mixture was cooled to room temperature and diluted with ethylacetate (100 mL) then washed with water (2×100 mL) and saturated aqueoussodium chloride, dried over magnesium sulfate, filtered and concentratedin vacuo. The crude material was then purified by silica gelchromatography (0-20% ethyl acetate in hexanes) to obtain the desiredproduct (46.0 mg, 10.0% yield). ¹H NMR (300 MHz, CDCl₃): δ 8.22 (dd,J=4.4, 1.5 Hz, 1H), 7.48 (dd, J=8.4, 4.4 Hz, 1H), 7.41 (dd, J=8.4, 1.5Hz, 1H), 7.31-7.19 (m, 2H), 7.05-6.95 (m, 2H), 2.39 (s, 3H); ¹³C NMR (75MHz, CDCl₃, partial): δ 152.16, 146.82, 141.31, 135.46, 130.85, 128.53,128.07, 119.74, 20.78.

Part B—Preparation of 3-(4-(bromomethyl)phenoxy)-2-nitropyridine

A solution of the product of Example 56A (0.039 g, 0.170 mmol),N-bromosuccinimide (35.0 mg, 0.200 mmol), and benzoyl peroxide (1 mg) in1,2-dichloroethane (4.0 mL) was heated to reflux and maintained 2 h. Theresulting mixture was cooled to room temperature and diluted withdichloromethane (20 mL), the organic layer separated then washed withwater (2×20 mL) and saturated aqueous sodium chloride, dried overmagnesium sulfate, filtered and concentrated. The crude yellow oil wasthen purified by silica gel chromatography (10-40% ethyl acetate inhexanes) to obtain the desired product as a faint yellow oil (45.0 mg,85.6% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.30 (dd, J=4.3, 1.6 Hz, 1H),7.59-7.43 (m, 4H), 7.12-7.02 (m, 2H), 4.52 (s, 2H); ¹³C NMR (75 MHz,CDCl₃, partial) δ 154.79, 145.77, 142.31, 135.07, 131.13, 129.28,128.74, 119.64, 32.33.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-nitropyridin-3-yl)oxy)benzyl)oxy)pyridazin-3(2H)-one

Prepared according to General Method B, using2-(tert-butyl)-4-chloro-5-pyridrazin-3(2H)-one (21.0 mg, 0.100 mmol),the product of Example 56B (31.0 mg, 0.100 mmol), and cesium carbonate(33.0 mg, 0.100 mmol) in dimethylformamide (1.0 mL) at 80° C. Isolatedyield—20.0 mg; 46.4%. ¹H NMR (300 MHz, CDCl₃): δ 8.22 (dd, J=4.3, 1.7Hz, 1H), 7.68 (s, 1H), 7.54-7.34 (m, 4H), 7.04 (d, J=8.7 Hz, 2H), 5.23(s, 2H), 1.57 (s, 9H); ¹³C NMR (75 MHz, CDCl₃, partial): δ 158.95,155.27, 153.50, 145.64, 142.47, 131.98, 129.45, 129.39, 128.79, 124.98,119.72, 118.54, 71.17, 66.53, 27.86. HRMS Calcd. for C₂₀H₁₉ ³⁵ClN₄O₅(M+H): 431.1117; found: 431.1110.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoropyridin-3-yl)oxy)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 56C (12.0 mg, 0.030 mmol),potassium fluoride (3.5 mg, 0.06 mmol), and Kryptofix™ (26.0 mg, 0.070mmol) in dimethylsulfoxide (2.0 mL) was heated to 125° C. and maintained30 min. The resulting mixture was cooled to room temperature and dilutedwith ethyl acetate (40 mL) then washed with water (2×40 mL) andsaturated aqueous sodium chloride, dried over magnesium sulfate,filtered and concentrated. The crude material was then purified bypreparative thin layer chromatography on silica (1% methanol indichloromethane) to obtain the desired product (9.0 mg, 74.3% yield). ¹HNMR (300 MHz, CDCl₃): δ 7.94 (d, J=4.7 Hz, 1H), 7.67 (s, 1H), 7.47-7.30(m, 3H), 7.12 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 7.02-6.90 (m, 2H), 5.21 (s,2H), 1.57 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 159.00, 156.99, 156.75,153.80, 153.60, 141.76 (d, J_(CF)=13.5 Hz), 130.60 (d, J_(CF)=3.8 Hz),130.46, 129.12, 125.09, 122.19, 118.50, 118.03, 71.37, 66.47, 27.87; ¹⁹FNMR (282 MHz, CDCl₃): δ −81.30 (d, J=9.8 Hz). HRMS Calcd. for C₂₀H₁₉³⁵ClFN₃O₃(M+H): 404.1172; found: 404.1176.

Example 57 Preparation of 3-fluoropropyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoatePart A—Preparation of 3-(tosyloxy) propyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

A solution of methyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate³(0.702 g, 2.00 mmol) in tetrahydrofuran/water (10.0 mL; 4:1 v/v) wascooled to 0° C. and treated with lithium hydroxide hydrate (0.252 g,6.00 mmol) in one portion. After 0.25 h, the now opaque solution waswarmed to ambient temperature and maintained 16 h. The resultingsolution was then diluted with water (50 mL), with transfer to aseparatory funnel, washed with diethyl ether (3×50 mL), and acidifiedwith 1 M hydrochloric acid. The now acidic solution was further washedwith warm ethyl acetate (3×50 mL) and the combined ethyl acetate washesdried over magnesium sulfate, filtered and concentrated in vacuo to awhite powder. Subsequent recrystallization from hot ethylacetate/pentane afforded the purified4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoicacid as colorless needles.

The intermediate acid thus obtained was dissolved in drydimethylformamide (20.0 mL) then successively treated withpropane-1,3-diyl bis(4-methylbenzenesulfonate) (1.15 g, 3.00 mmol) andpotassium carbonate (0.415 g, 3.00 mmol) in one portion at ambienttemperature. After 5 h, the resulting suspension was partitioned betweenethyl acetate and water (50 mL each), with transfer to a separatoryfunnel, and the layers separated. The aqueous layer was then washed withethyl acetate (2×50 mL) and the combined ethyl acetate washes dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial was then purified by chromatography on silica using a stepgradient from 7:3 pentane/ethyl acetate (500 mL) to 3:2 pentane/ethylacetate (1000 mL). The main product peak eluting 1075-1275 mL wascollected, pooled and concentrated in vacuo to a colorless oil (0.566 g,1.03 mmol; 51.6%). ¹H NMR: (300 MHz, DMSO-d₆) δ 8.25 (1H, s), 7.89 (2H,AA′BB′, J_(AB)=8.3 Hz, J_(AA′)=2.0 Hz), 7.75 (2H, AA′BB′, J_(AB)=8.3 Hz,J_(AA′)=2.0 Hz), 7.57 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=7.9 Hz), 5.57(2H, s), 4.23 (2H, d, J=5.9 Hz), 4.18 (2H, t, J=5.7 Hz), 2.27 (3H, s),2.04 (2H, tt, J=5.9, 5.9 Hz), 1.57 (9H, s). ¹³C NMR: (75 MHz, DMSO-d₆) δ165.0, 157.7, 153.7, 144.8, 140.8, 132.0, 130.0, 129.5, 129.4, 127.5,126.1, 115.8, 70.7, 67.5, 65.4, 60.5, 27.5, 27.4, 20.9. HRMS Calcd. forC₂H₂₉ ³⁵ClN₂O₇S (M+H): 549.1457; found: 549.1467. TLC: R_(f) 0.33(silica gel, 1:1 pentane/ethyl acetate, uv).

Part B—Preparation of 3-fluoropropyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate

A solution of methyl4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzoate³(0.702 g, 2.00 mmol) in tetrahydrofuran/water (10.0 mL; 4:1 v/v) wascooled to 0° C. and treated with lithium hydroxide hydrate (0.252 g,6.00 mmol) in one portion. After 0.25 h, the now opaque solution waswarmed to ambient temperature and maintained 16 h. The resultingsolution was then diluted with water (50 mL), with transfer to aseparatory funnel, washed with diethyl ether (3×50 mL), and acidifiedwith 1 M hydrochloric acid. The now acidic solution was further washedwith warm ethyl acetate (3×50 mL) and the combined ethyl acetate washesdried over magnesium sulfate, filtered and concentrated in vacuo to awhite powder.

The intermediate acid thus obtained was dissolved in drydimethylformamide (5.00 mL) then successively treated with3-fluoropropyl 4-methylbenzenesulfonate (0.697 g, 3.00 mmol) andpotassium carbonate (0.415 g, 3.00 mmol) in one portion at ambienttemperature. After 0.25 h, the resulting solution was warmed to 55° C.,maintained 1.5 h, then cooled to ambient temperature and diluted withethyl acetate (150 mL each) with transfer to a separatory funnel. Theethyl acetate solution thus obtained was then washed with saturatedaqueous sodium chloride (5×50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo to an amber oil. The crude materialwas then purified by chromatography on silica (30×200 mm) using 3:1pentane/ethyl acetate. The main product peak eluting 300-560 mL wascollected, pooled and concentrated in vacuo to a white solid (0.680 g,1.71 mmol; 85.7%). ¹H NMR: (300 MHz, DMSO-d₆) δ 8.23 (1H, s), 8.03 (2H,AA′BB′, J_(AB)=8.5 Hz, J_(AA′)=1.9 Hz), 7.60 (2H, AA′BB′, J_(AB)=8.7 Hz,J_(BB′)=1.9 Hz), 5.56 (2H, s), 4.61 (2H, dt, J=47.2, 5.9 Hz), 4.38 (2H,t, J=6.3 Hz), 2.11 (2H, dtt, J=25.9, 6.1, 6.1 Hz) 1.57 (9H, s). ¹⁹F NMR:(282 MHz, DMSO-d₆) 5-220.4 (1F, tt, J=47.1, 25.8 Hz). ¹³C NMR: (75 MHz,DMSO-d₆) δ 165.3, 157.7, 153.7, 140.8, 129.6, 129.5, 127.5, 126.1,115.8, 80.9 (d, J=161.9 Hz), 70.7, 65.4, 61.0 (d, J=5.6 Hz), 29.2 (d,J=19.6 Hz), 27.4. HRMS Calcd. for C₁₉H₂₂ ³⁵ClFN₂O₄ (M+H): 397.1325;found: 397.1330. TLC: R_(f) 0.24 (silica gel, 3:1 pentane/ethyl acetate,uv).

Example 58 Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-(2-fluoroethoxy)propan-2-yl)benzyl)oxy)pyridazin-3(2H)-one Part A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4,5-dichloropyridazin-3(2H)-one (0.995 g,4.50 mmol) and 2-(4-(hydroxymethyl)phenyl)propan-2-ol (0.499 g, 3.00mmol; e.g., see Machacek, Michelle R.; Haidle, Andrew; Zabierek, AnnaA.; Konrad, Kaleen M.; Altman, Michael D. (Merck & Co., Inc.)Preparation of thiazolecarboxamides as inhibitors of Janus kinases. PCTInt. Appl. WO 2010/011375. Jan. 28, 2010) in dry dimethylformamide (15.0mL) was treated with cesium carbonate (1.96 g, 6.00 mmol) in one portionat ambient temperature. The resulting suspension was then immersed in apre-heated oil bath and maintained 2.5 h at 80° C. Left unattended, thesuspension was cooled to ambient temperature and maintained 20 h. Theresulting suspension was then partitioned between ethyl acetate (150 mL)and water (25 mL), with transfer to a separatory funnel, and the layersseparated. The ethyl acetate layer was then washed with saturatedaqueous sodium chloride (5×25 mL), dried over magnesium sulfate,filtered and concentrated in vacuo to an amber oil. The crude materialwas then purified by chromatography on silica (40×170 mm) using 3:2hexanes/ethyl acetate. The main product peak eluting 400-700 mL wascollected, pooled and concentrated in vacuo to a white solid. Subsequentrecrystallization from hot ethyl acetate/pentane afford the desiredproduct as colorless needles (0.682 g, 1.95 mmol; 64.9%). ¹H NMR: (300MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.51 (2H, AB, J_(AB)=8.3 Hz), 7.39 (2H,AB, J_(AB)=8.3 Hz), 5.42 (s, 2H), 5.01 (s, 1H), 1.57 (s, 9H), 1.42 (s,6H). ¹³C NMR: (75 MHz, DMSO-d₆) δ 157.8, 153.9, 151.0, 132.8, 127.4,126.2, 124.8, 115.5, 71.4, 70.5, 65.3, 31.8, 27.4. HRMS Calcd. forC₁₈H₂₃ ³⁵ClN₂O₃ (M+H): 351.1470; found: 351.1474. TLC: R_(f) 0.16(silica gel, 7:3 hexanes/ethyl acetate, CAM).

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(2-(2-fluoroethoxy)propan-2-yl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of part A (0.105 g, 0.300 mmol) in2-fluoroethanol (1.75 mL) was treated with 11.4 mg p-toluenesulfonicacid hydrate (0.06 mmol; 20 mol %) in one portion at ambienttemperature. After 24 h, all volatiles were removed in vacuo, and theresidue directly purified by chromatography on silica (30×185 mm) using4:1 hexanes/ethyl acetate. The main product peak eluting 360-450 mL wascollected, pooled and concentrated in vacuo to a colorless oil (81.2 mg,0.205 mmol; 68.3%). ¹H NMR: (300 MHz, DMSO-d₆) δ 8.28 (1H, s), 7.55-7.39(4H, m), 5.44 (2H, s), 4.62-4.52 (1H, m), 4.47-4.36 (1H, m), 3.46-3.34(1H, m), 3.36-3.25 (1H, m), 1.58 (9H, s), 1.49 (6H, s). ¹⁹F NMR: (282MHz, DMSO-d₆) δ −222.01 (1F, tt, J=47.8, 30.6 Hz). ¹³C NMR: (75 MHz,DMSO-d₆) δ 157.8, 153.9, 146.3, 133.9, 127.7, 126.1, 125.8, 115.5, 83.17(d, J=166.3 Hz), 76.3, 71.2, 65.3, 61.89 (d, J=19.2 Hz), 28.0, 27.4.HRMS Calcd. for C₂₀H₂₆ ³⁵ClFN₂O₃(M+H): 397.1689; found: 397.1695. TLC:R_(f) 0.51 (silica gel, 3:2 hexanes/ethyl acetate, uv).

Example 59 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)phenyl)ethynyl)pyridazin-3(2H)-onePart A—Preparation of (4-(1,3-dioxolan-2-yl)phenyl)methanol

Methyl 4-formylbenzoate (4.92 g, 30.0 mmol) was dissolved in dry toluene(50.0 mL), successively treated with ethylene glycol (1.84 mL, 33.0mmol) and p-toluenesulfonic acid (57.1 mg, 0.300 mmol), then heated toreflux under Dean-Stark conditions; acetal formation was complete within1 h. The solution was then cooled to 22° C. and directly treated withsodium bis(2-methoxyethoxy)aluminum hydride (45.0 mmol; 12.7 mL of a70.3 wt. % solution in toluene) at a rate of 0.5 mL/min using a syringepump. Upon completion of the addition, the resulting solution was cooledto 0° C., carefully treated with a saturated aqueous solution ofpotassium sodium tartrate (100 mL) then vigorously stirred 1 h; steadyformation of a clear solution was observed. The resulting biphase wasthen diluted with ethyl acetate (50 mL), with transfer to a conicalfunnel, and the layers separated. The aqueous layer was then washed withethyl acetate (3×50 mL) and the combined ethyl acetate and toluenesolutions dried over magnesium sulfate, filtered and concentrated invacuo to a colorless oil. The crude product was then purified bychromatography on silica (50×135 mm) using 1:1 pentane/ethyl acetate.The main product peak eluting 425-725 mL was collected, pooled andconcentrated in vacuo to a colorless oil, which solidified in thefreezer (4.50 g, 83.2% over two steps). ¹H NMR: (600 MHz, CDCl₃) δ 7.48(2H, AB, J_(AB)=8.1 Hz), 7.39 (2H, AB, J_(AB)=8.3 Hz), 5.82 (1H, s),4.71 (2H, d, J=6.0 Hz), 4.08 (4H, AA′BB′, J_(AA′)=J_(BB′)=7.2 Hz,J_(AB)=−7.5 Hz, J_(AB′)=6.4 Hz), 1.63 (1H, t, J=6.0 Hz). ¹³C NMR: (75MHz, CDCl₃) δ 142.0, 137.2, 126.8, 126.6, 103.5, 65.3, 64.9.

Part B—Preparation of 4-((2-fluoroethoxy)methyl)benzaldehyde

A solution of the product of Example 59A (1.80 g, 10.0 mmol) in dryacetonitrile (50.0 mL) was successively treated with1-bromo-2-fluoroethane (3.73 mL, 50.0 mmol) and powdered potassiumhydroxide (5.61 g, 0.100 mol) in one portion at ambient temperature.After 0.5 h, the resulting suspension was warmed to 80° C. thenmaintained 2.5 h. After cooling to ambient temperature, the suspensionwas diluted with water (100 mL), with transfer to a separatory funnelthen washed with ethyl acetate (3×100 mL). The combined ethyl acetatewashes were dried over magnesium sulfate, filtered and concentrated invacuo to a colorless that was directly purified by chromatography onsilica (50×195 mm) using 1:1 pentane/diethyl ether to afford2-(4-((2-fluoroethoxy)methyl)phenyl)-1,3-dioxolane as a colorless oil(2.04 g, 9.02 mmol; 90.2%). The purified acetal (0.423 g, 2.00 mmol) wasthen dissolved in wet acetone (8.00 mL) and directly treated with dilutehydrochloric acid (2.00 mmol; 2.00 mL of a 1.0 N solution in water) atambient temperature. After stirring 18 h, the resulting mixture waspartitioned between diethyl ether and saturated aqueous sodiumbicarbonate (50 mL each), with transfer to a conical funnel, and thelayers separated. The aqueous layer was then washed with diethyl ether(2×50 mL) and the combined ethereal solutions dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification bybulb-to-bulb distillation under reduced pressure afforded the titlecompound as a colorless oil (0.340 g, 1.87 mmol; 93.4%).

Part C—Preparation of 1-ethynyl-4-((2-fluoroethoxy)methyl)benzene

Carbontetrabromide (1.06 g, 3.20 mmol), zinc dust (0.210 g, 3.20 mmol)and triphenylphosphine (0.840 g, 3.20 mmol) were added to a solution ofthe product of Example 59B (0.290 g, 1.60 mmol) in dichloromethane (10.0mL) at ambient temperature. The crude dibromo intermediate was isolatedusing standard workup procedures, dissolved in dry tetrahydrofuran (8.00mL) then cooled to −78° C. and treated with a solution of n-butyllithiumin tetrahydrofuran (2.00 mL). The resulting mixture was then warmed toambient temperature, treated with water and extracted with ethylacetate. The ethyl acetate solution was washed with water and saturatedaqueous sodium chloride then dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude material thus obtained was thenpurified by chromatography on silica (12 g) using 9:1 hexanes/ethylacetate, to afford the title compound (0.190 g, 66.6%). ¹H NMR (300 MHz,DMSO-d₆) δ 7.50-7.44 (m, 2H), 7.38-7.32 (m, 2H), 4.67-4.63 (m, 1H), 4.55(s, 2H), 4.51-4.47 (m, 1H), 4.16 (s, 1H), 3.76-3.72 (m, 1H), 3.66-3.62(m, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ 139.19, 131.60, 127.51, 120.72,83.68 (d, J=51.8 Hz), 81.82, 80.62, 71.41, 69.10 (d, J=18.8 Hz).

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)phenyl)ethynyl)pyridazin-3(2H)-one

A solution of 1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yltrifluoromethane sulfonate (0.175 g, 0.523 mmol), the product of Example59C (95.0 mg, 0.533 mmol), trans-dichloro(triphenylphosphine)palladium(II) (11.0 mg, 0.0157 mmol; 3.0 mol %), copper(I) iodide (30.0 mg, 0.158mmol), n-tetrabutylammonium iodide (0.576 g, 1.55 mmol) andtriethylamine (220 μL, 1.58 mmol) in anhydrous tetrahydrofuran (5.00 mL)was stirred 2 h at ambient temperature then diluted with ethyl acetate,and filtered through Celite with transfer to a separatory funnel. Theethyl acetate solution was then washed with water and saturated aqueoussodium chloride, dried over magnesium sulfate, filtered and concentratedin vacuo. The crude material thus obtained was then purified bychromatography on silica (4 g) using 3:1 hexanes/ethyl acetate, toafford the title compound (90.0 mg, 46.5%). ¹H NMR (300 MHz, DMSO-d₆) δ8.06 (s, 1H), 7.66-7.63 (m, 2H), 7.48-7.45 (m, 2H), 4.68-4.66 (m, 1H),4.61 (s, 2H), 4.52-4.50 (m, 1H), 3.79-3.76 (m, 1H), 3.69-3.66 (m, 1H),1.60 (s, 9H). ¹³C NMR (75 MHz, DMSO-d₆) δ 155.85, 141.13, 136.51,134.28, 131.97, 127.71, 124.57, 119.20, 102.11, 84.02, 81.58 (d, J=36.0Hz), 71.33, 69.25 (d, J=19.5 Hz), 65.89, 27.30. ¹⁹F NMR (282 MHz,DMSO-d₆) δ −221.61 (tt, J=48.0, 31.1 Hz). HRMS Calcd. for C₁₉H₂₀³⁵ClFN₂O₂ (M+H): 363.1270; found: 363.1266.

Example 60 Preparation of(E)-2-(tert-butyl)-4-chloro-5-(4-((2-fluoroethoxy)methyl)styryl)pyridazin-3(2H)-onePart A—Preparation of 1-((2-fluoroethoxy)methyl)-4-vinylbenzene

A suspension of methyltriphenylphosphonium bromide (0.260 g, 0.728 mmol)and sodium hydride (80.0 mg, 3.33 mmol) in dry tetrahydrofuran (2.50 mL)was cooled to 0° C. then treated with the product of Example 59A (0.110g, 0.604 mmol). The resulting mixture then warmed slowly to ambienttemperature as the ice melted. After 2 h total, the suspension wasdiluted with diethyl ether with transfer to a separatory funnel thenwashed with water and saturated aqueous sodium chloride, dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial thus obtained was then purified by chromatography on silica (4g) using 9:1 hexanes/ethyl acetate, to afford the title compound (40.0mg, 36.7%). ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.29 (m, 2H), 7.24 (d, J=8.2Hz, 2H), 6.64 (dd, J=17.6, 10.9 Hz, 1H), 5.67 (dd, J=17.6, 1.0 Hz, 1H),5.17 (dd, J=10.9, 0.9 Hz, 1H), 4.64-4.56 (m, 1H), 4.52 (s, 2H),4.47-4.38 (m, 1H), 3.75-3.65 (m, 1H), 3.64-3.55 (m, 1H). ¹⁹F NMR (282MHz, CDCl₃) δ −223.12 (tt, J=48.0, 31.1 Hz).

Part B—Preparation of(E)-2-(tert-butyl)-4-chloro-5-(4-((2-fluoroethoxy)methyl)styryl)pyridazin-3(2H)-one

A solution of 1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yltrifluoromethane sulfonate (0.180 g, 0.538 mmol), the product of Example60A (0.140 g, 0.777 mmol),trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (40.0 mg, 0.057mmol; 7.3 mol %) and triethylamine (120 μL, 0.860 mmol) in drydimethylformamide (5.00 mL) was warmed to 110° C. and maintained 2 h.After cooling to ambient temperature, the resulting mixture was dilutedwith ethyl acetate, and filtered through Celite with transfer to aseparatory funnel. The ethyl acetate solution was then washed with waterand saturated aqueous sodium chloride, dried over magnesium sulfate,filtered and concentrated in vacuo. The crude material thus obtained wasthen purified by chromatography on silica (4 g) using 4:1 hexanes/ethylacetate, to afford the title compound (50.0 mg, 25.5%). ¹H NMR (300 MHz,CDCl₃) δ 8.04 (s, 1H), 7.60-7.57 (m, 2H), 7.44-7.41 (m, 2H), 7.29 (d,J=6.0 Hz, 1H), 4.72-4.69 (m, 1H), 4.65 (s, 2H), 4.56-4.53 (m, 1H),3.84-3.81 (m, 1H), 3.74-3.71 (m, 1H), 1.69 (s, 9H). ¹³C NMR (75 MHz,DMSO-d₆) δ 157.59, 139.74, 136.58, 135.09, 134.98, 132.73, 130.83,128.16, 127.58, 120.07, 83.08 (d, J=168.0 Hz), 72.87, 69.42 (d, J=19.5Hz), 66.08, 27.85. ¹⁹F NMR (282 MHz, DMSO) δ −223.04 (tt, J=47.9, 28.2Hz). HRMS Calcd. for C₁₉H₂₂ ³⁵ClFN₂O₂(M+H): 365.1427; found: 365.1421.

Example 61 Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)phenyl)ethynyl)pyridazin-3(2H)-onePart A—Preparation of (E)-methyl4-(2-(1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)vinyl)benzoate

A solution of 1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yltrifluoromethane sulfonate (0.400 g, 1.20 mmol), methyl 4-vinylbenzoate(0.210 g, 1.29 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium(II)(40.0 mg, 0.057 mmol; 4.8 mol %) and triethylamine (80.0 μL, 0.574mmol) in dry dimethylformamide (2.00 mL) was warmed to 110° C. andmaintained 2 h. After cooling to ambient temperature, the resultingmixture was diluted with ethyl acetate, and filtered through Celite withtransfer to a separatory funnel. The ethyl acetate solution was thenwashed with water with and saturated aqueous sodium chloride, dried overmagnesium sulfate, filtered and concentrated in vacuo.

The crude material thus obtained was then purified by chromatography onsilica (12 g) using 4:1 hexanes/ethyl acetate, to afford the titlecompound (80.0 mg, 19.2%). ¹H NMR (300 MHz, CDCl₃) δ 8.12-8.08 (m, 2H),8.03 (s, 1H), 7.68-7.62 (m, 2H), 7.48-7.32 (m, 2H), 3.96 (s, 3H), 1.70(s, 9H).

Part B—Preparation of methyl4-(2-(1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)ethyl)benzoate

A solution of the product of Example 61A (50.0 mg, 0.144 mmol) in 2:1methanol/dichloromethane (15.0 mL) was treated with platinum(II) oxide(20.0 mg, 0.088 mmol) in one portion at ambient temperature. Theresulting suspension was stirred under a hydrogen atmosphere thenfiltered through a mixture of Celite and silica gel and the resultingfiltrate concentrated in vacuo. The crude material thus obtained wasthen purified by chromatography on silica (4 g) using 4:1 hexanes/ethylacetate, to afford the title compound (30.0 mg, 59.7%). ¹H NMR (300 MHz,CDCl₃) δ 8.00 (d, 2H, J=8.3 Hz), 7.47 (s, 1H), 7.28 (d, 2H, J=8.2 Hz),3.93 (s, 3H), 3.00-2.94 (m, 4H), 1.66 (s, 9H).

Part C—Preparation of2-(tert-butyl)-4-chloro-5-(4-(hydroxymethyl)phenethyl)pyridazin-3(2H)-one

A solution of the product of Example 61B (30.0 mg, 0.086 mmol) intetrahydrofuran (2.00 mL) was cooled to 0° C. then treated with lithiumaluminum hydride (0.4 mL, 0.4 mmol of a 1 M solution in tetrahydrofuran)and warmed to ambient temperature. After 1 h, the resulting mixture wasdiluted with water (20 mL), the aqueous layer separated then washed withdichloromethane (3×20 mL). The combined organic washes were furtherwashed with saturated aqueous sodium chloride then dried over magnesiumsulfate, filtered and concentrated to in vacuo to yield the titlecompound (20.0 mg) that was used without additional purification in thesubsequent reaction.

Part D—Preparation of5-(4-(bromomethyl)phenethyl)-2-(tert-butyl)-4-chloropyridazin-3(2H)-one

A solution of the product of Example 61C (20.0 mg, 0.062 mmol) indichloromethane (1.00 mL) was directly treated with phosphoroustribromide (0.030 mmol; 30 μL of a 1 M solution in dichloromethane) thenstirred 1 h at ambient temperature. The resulting mixture was thendiluted with dichloromethane (20 mL), with transfer to a separatoryfunnel, and washed with water and saturated aqueous sodium chloride,dried over magnesium sulfate, filtered, and concentrated in vacuo toyield the title compound (20.0 mg) that was used without additionalpurification in the subsequent reaction. ¹H NMR (300 MHz, CDCl₃) δ 7.49(s, 1H), 7.33-7.28 (m, 2H), 7.23-7.17 (m, 2H), 4.56 (s, 2H), 3.80-3.74(m, 2H), 3.63-3.57 (m, 2H), 2.93 (s, 4H), 1.67 (s, 9H).

Part E—Preparation of2-(tert-butyl)-4-chloro-5-(4-((2-hydroxyethoxy)methyl)phenethyl)pyridazin-3(2H)-one

A suspension of sodium hydride (0.20 mmol; 8.0 mg of a 60% dispersion inmineral oil) and ethylene glycol (10.0 μL, 0.18 mmol), was treated witha solution of the product of Example 61D (20.0 mg, 0.052 mmol) in drytetrahydrofuran (2.00 mL) and the resulting mixture heated to reflux.After 4 h, the reaction mixture was cooled to ambient temperature,diluted with diethylether (20 mL) then transferred to a separatoryfunnel, washed with water and saturated aqueous sodium chloride, driedover magnesium sulfate, filtered and concentrated in vacuo. The crudematerial thus obtained was then purified by chromatography on silica (4g) using 7:3 hexanes/ethyl acetate, to afford the title compound (5.5mg, 29.0%). ¹H NMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 7.32-7.28 (m, 2H),7.22-7.18 (m, 2H), 4.57 (s, 2H), 3.80-3.76 (m, 2H), 3.63-3.59 (m, 2H),2.93 (s, 4H), 1.67 (s, 9H).

Part F—Preparation of2-((4-(2-(1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)ethyl)benzyl)oxy)ethyl 4-methylbenzenesulfonate

Prepared according the General Method D, using the product of Example61E (5.5 mg, 0.015 mmol), p-toluenesulfonyl chloride (8.0 mg, 0.042mmol), 4-dimethylaminopyridine (one crystal), and triethylamine (0.010mL, 0.072 mmol). Isolated yield—5.0 mg; 64.2%. ¹H NMR (300 MHz, CDCl₃) δ7.87-7.79 (m, 2H), 7.50 (s, 1H), 7.39-7.30 (m, 2H), 7.25-7.17 (m, 4H),4.49 (s, 2H), 4.27-4.17 (m, 2H), 3.73-3.63 (m, 2H), 2.93 (s, 4H), 2.46(s, 3H), 1.67 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 157.53, 144.74, 140.72,139.49, 135.95, 135.18, 134.90, 133.11, 129.78, 128.35, 128.05, 127.96,72.96, 69.21, 67.52, 66.26, 33.56, 32.69, 27.77, 21.63.

Part G—Preparation of2-(tert-butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)phenyl)ethynyl)pyridazin-3(2H)-one

A solution of the product of Example 59C (40.0 mg, 0.110 mmol) in 1:1ethyl acetate/hexanes (10.0 mL) was treated with 5% palladium on calciumcarbonate, poisoned with lead (20.0 mg, 0.094 mmol) in one portion atambient temperature. The resulting suspension was stirred under ahydrogen atmosphere then filtered through a mixture of Celite and silicagel and the resulting filtrate concentrated in vacuo. The crude materialthus obtained was then purified by chromatography on silica (4 g) using4:1 hexanes/ethyl acetate, to afford the title compound (20.0 mg,49.6%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.29-7.22 (m, 4H),4.65-4.62 (m, 1H), 4.50 (s, 2H), 4.49-4.46 (m, 1H), 3.72-3.69 (m, 1H),3.62-3.59 (m, 1H), 2.91-2.89 (m, 4H), 1.58 (s, 9H). ³C NMR (75 MHz,DMSO-d₆) δ 156.34, 141.37, 139.41, 136.10, 135.56, 133.71, 128.15,127.71, 82.95 (d, J=164 Hz), 71.78, 68.82 (d, J=18.8 Hz), 65.27, 32.62,31.78, 27.34. ¹⁹F NMR (282 MHz, DMSO) δ −221.51 (tt, J=48.0, 31.1 Hz).HRMS Calcd. for C₁₉H₂₄ ³⁵ClFN₂O₂ (M+H): 367.1583; found: 367.1580.

Example 62 Preparation of Silyl Derivatives Part A—Preparation of2-(tert-butyl)-4-chloro-5-((4-(di-tert-butylsilyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.476 g, 2.36 mmol) in tetrahydrofuran (23.6 mL) was successivelytreated with (4-(di-tert-butylsilyl) phenyl) methanol (0.706 g, 2.82mmol; e.g., see James, D.; Escudier, J.-M.; Amigues, E.; Schulz, J.;Virty, C.; Bordenave, T.; Szlosek-pinaud, M.; Fouquet, E. A “clickchemistry” approach to the efficient synthesis of modified nucleosidesand oligonucleotides for PET imaging. Tetrahedron Lett., 2010, 51,1230-1232), triphenylphosphine (0.929 g, 3.54 mmol), anddiethylazodicarboxylate (0.617 g, 3.54 mmol) at ambient temperature.After 90 min, the resulting mixture was diluted with water (50 mL), withtransfer to a separatory funnel and the aqueous layer separated thenwashed with ethyl acetate (3×100 mL). The combined organic washes weredried over sodium sulfate, filtered, and concentrated in vacuo to anorange oil. The crude material was then triturated with diethyl etherfor 2 h and the resulting suspension filtered to remove the suspendedtriphenylphosphine oxide. The filtrate was purified by chromatography onsilica using a 0-50% ethyl acetate in hexanes gradient to afford thetitle compound as a white solid (0.227 g, 22.1%). ¹H NMR: (300 MHz,CDCl₃) δ 7.76 (s, 1H), 7.64 (d, 2H, J=8.12 Hz), 7.40 (d, 2H, J=8.12 Hz),5.34 (s, 2H), 3.90 (s, 1H), 1.55 (s, 9H), 1.07 (s, 18H); ¹³C NMR: (75MHz, CDCl₃) δ 159.04, 153.78, 136.49, 136.29, 135.43, 126.03, 125.18,98.55, 71.91, 66.38, 28.87, 27.87, 18.99. HRMS Calcd. forC₂₃H3₅₃₅ClN₂O₂Si (M+Na): 429.1736; found: 429.1729.

Part B—Preparation of2-(tert-butyl)-4-chloro-5-((4-(di-tert-butylfluorosilyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 62A (5.0 mg, 0.011 mmol) indimethylsulfoxide (0.3 mL) was added to a mixture of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (8.7 mg,0.023 mmol) and potassium fluoride (0.6 mg, 0.011 mmol) then warmed to35° C. After 10 min, the resulting mixture was cooled to ambienttemperature then diluted with water (0.5 mL) with transfer to aseparatory funnel. The aqueous layer was then washed with ethyl acetate(3×2 mL) and the combined washes dried over sodium sulfate, filtered andconcentrated in vacuo to an oil. The crude material thus obtained wasthen purified by preparative thin-layer chromatography on silica using4:1 hexanes/ethyl acetate to afford the title compound as a white solid(3.2 mg, 70.6%; e.g., see Mu L.; Hoehne, A.; Schubiger, P. A.; Ametamey,S. M.; Graham, K.; Cyr, J. E.; Dinkelborg, L.; Stellfeld, T.;Srinivasan, A.; Voigtmann, U.; Klar, U. Silicon-based Building blocksfor one step 18F-radiolabeling of peptides for PET imaging. Angew. Chem.Int. Ed. 2008, 47, 4922-4925). ¹H NMR: (300 MHz, CDCl₃) δ 7.72-7.59 (m,3H), 7.33 (d, 2H, J=8.14 Hz), 5.24 (s, 2H), 1.57 (s, 9H), 0.97 (s, 18H).¹³C NMR (75 MHz, CDCl₃, partial) δ 158.03, 152.73, 135.12, 133.66 (d,J=4.5 Hz), 125.09, 124.12, 98.97, 70.79, 65.43, 26.87, 26.29, 19.23 (d,J=12.0 Hz). ¹⁹F NMR: (282 MHz, CDCl₃) δ −188.74 (1F, s). HRMS Calcd. forC₂₃H₃₄ ³⁵ClFN₂O₂Si (M+H): 453.2135; found: 453.2139.

Part C—Preparation of2-(tert-butyl)-4-chloro-5-((4-(diisopropylsilyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of 2-(tert-butyl)-4-chloro-5-hydroxypyridrazin-3(2H)-one(0.476 g, 2.36 mmol) in tetrahydrofuran (23.6 mL) was successivelytreated with (4-(diisopropylsilyl) phenyl) methanol (0.627 g, 2.82 mmol;e.g., see James, D.; Escudier, J.-M.; Amigues, E.; Schulz, J.; Virty,C.; Bordenave, T.; Szlosek-pinaud, M.; Fouquet, E. A “click chemistry”approach to the efficient synthesis of modified nucleosides andoligonucleotides for PET imaging. Tetrahedron Lett., 2010, 51,1230-1232), triphenylphosphine (0.929 g, 3.54 mmol), anddiethylazodicarboxylate (0.617 g, 3.54 mmol) at ambient temperature.After 2 h, the resulting mixture was diluted with water (50 mL), withtransfer to a separatory funnel and the aqueous layer separated thenwashed with ethyl acetate (3×100 mL). The combined organic washes weredried over sodium sulfate, filtered, and concentrated in vacuo to anoil. The crude material was then triturated with diethyl ether for 2 hand the resulting suspension filtered to remove the suspendedtriphenylphosphine oxide. The filtrate was purified by chromatography onsilica using a 0-50% ethyl acetate in hexanes gradient to afford thetitle compound as a white solid (0.259 g, 27.0% yield). ¹H NMR: (300MHz, CDCl₃) 57.55 (s, 1H), 7.38 (d, 2H, J=8.03 Hz), 7.19 (d, 2H, J=8.12Hz), 5.12 (s, 2H), 3.77 (m, 1H), 1.46 (s, 9H), 1.05 (m, 2H), 0.87 (dd,J=6.0 Hz, 6H), 0.82 (dd, J=6.0 Hz, 6H). ³C NMR (75 MHz, CDCl₃) δ 159.03,153.76, 136.01, 135.63, 135.21, 126.18, 125.14, 71.90, 66.39, 27.87,18.61, 18.45, 10.65. HRMS Calcd. for C₂₁H₃₁ ³⁵ClN₂₂Si (M+H): 407.1916;found: 407.1922.

Part D—Preparation of2-(tert-butyl)-4-chloro-5-((4-(diisopropylfluorosilyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 62C (5.0 mg, 0.011 mmol) intetrahydrofuran (0.3 mL) was added to a solution of tetrabutylammoniumfluoride (0.011 mmol; 0.011 mL of a 1 M solution in tetrahydrofuran at−78° C. After 6 h, the resulting mixture was warmed to −20° C. andmaintained an additional 20 h. After warming to ambient temperature, thecrude mixture was directly purified by preparative thin-layerchromatography on silica using 9:1 hexanes/ethyl acetate to afford thetitle compound as a colorless oil (4.2 mg, 82.4%). ¹H NMR: (300 MHz,CDCl₃) δ 7.66 (s, 1H), 7.58-7.49 (m, 2H), 7.37 (d, 2H, J=7.84 Hz), 5.24(s, 2H), 1.57 (s, 9H), 1.16-1.25 (m, 2H), 0.96-0.94 (m, 12H). ¹³C NMR(75 MHz, CDCl₃, partial) δ 159.01, 153.70, 136.53, 134.43 (d, J=3.7 Hz),126.29, 125.08, 71.76, 66.43, 27.87, 16.65, 16.62, 12.30 (d, J=12.7 Hz).¹⁹F NMR: (282 MHz, CDCl₃) δ −187.01 (t, J=5.6 Hz).

Example 63 Preparation of2-(tert-butyl)-4-chloro-5-((4-(4-fluorobutanoyl)benzyl)oxy)pyridazin-3(2H)-one

A solution of the product of Example 43D in 1,4-dioxane is treated with[(IPr)AuCl](e.g., see Marion, N.; Ramon, R.; Nolan, S. P.[(NHC)AuI]-Catalyzed Acid Free Hydration of Alkynes at Part-Per-MillionCatalyst Loadings. J. Am. Chem. Soc. 2009, 131, 448-449) and silverhexafluoroantiminate at ambient temperature. After 1 min, water is addedand the resulting mixture warmed to 120° C. and maintained overnight.After cooling to ambient temperature, all volatile materials are removedin vacuo and the residue purified by chromatography on silica to affordthe title compound.

Example 64 Part A—Preparation of Submitochondrial Particles from BovineHeart

Bovine heart mitochondria were prepared as described by Lester et al.(e.g., see Lester R. L.; Smith A. L. Studies on the electron transportsystem. 28. The mode of reduction of tetrazolium salts by beef heartmitochondria; role of coenzyme Q and other lipids. Biochim Biophys.Acta. 1961, 47, 475-96). In brief, bovine heart was minced and 200 g ofground heart tissue was suspended in 400 mL of 0.25 M sucrose, 0.01 MTris-C1, 1 mM Tris-succinate, and 0.2 mM ethylenediamine tetra-aceticacid (EDTA) and homogenized in a Waring blender. The homogenate wascentrifuged for 20 min at 1,200×g and the supernatant was centrifugedfor 15 min at 26,000×g resulting in a mitochondrial pellet. The proteinconcentration of the mitochondrial samples as measured by BioRad ProteinAssay Kit (BioRad Life Science Research, Hercules, Calif.) was adjustedto 20 mg/mL using 0.25 M sucrose, 10 mM Tris-acetate pH 7.5, 1.5 mMadenosine triphosphate (ATP), and 10 mM magnesium chloride. The sampleswere stored at −80° C.

Bovine submitochondrial particles (SMPs) were prepared from mitochondriaas described by Matsuno-Yagi et al. (e.g., see Matsuno-Yagi, A.; Hatefi,Y. Studies on the mechanism of oxidative phosphorylation. Catalytic sitecooperativity in ATP synthesis. J. Biol. Chem. 1985, 260, 11424-7). Inbrief, isolated bovine heart mitochondria were sonicated in batches of15 mL for 1 minute with a digital Branson sonifier (Branson, Danbury,Conn.) at 70% maximum output in an ice bath. The sonicated suspensionwas centrifuged at 16,000×g for 10 min, and the supernatant wascentrifuged at 150,000×g for 45 min at 4° C. The submitochondrial pelletwas resuspended in buffer containing 0.25 M Sucrose, 10 mM Tris-acetate,pH 7.5. The protein concentration was determined using the BioRadProtein Assay Kit (BioRad Life Science Research, Hercules Calif.), andthe samples were stored at −80° C., at a concentration of 20 mg/mL.

Part B—Submitochondrial Particle (SMP) Catalytic Activity and CompoundInhibition Assay

The procedure for determining catalytic activity of submitochondrialparticles was adapted from Satoh et al. (e.g., see Satoh T, Miyoshi H,Sakamoto K, Iwamura H.

Comparison of the inhibitory action of synthetic capsaicin analogueswith various NADH-ubiquinone oxidoreductases. Biochim Biophys Acta.1996, 1273, 21-30). NADH-DB reductase activity was measured using astirred cuvette in a spectrophotometer (Hewlett-Packard, Houston Tex.)at 37° C., as the rate of NADH oxidation at 340 nm (ε=5.4 mM⁻¹×cm⁻¹) for120 seconds. The final volume of the reaction was 2.5 mL, containing 50mM K₂HPO₄ (pH 7.4), 0.4 μM Antimycin A, and 2 mM potassium cyanide. Thefinal SMP concentration was 45 μg/mL. The enzyme reaction was initiatedby the addition of 100 μM decyl ubiquinone and 50 μM NADH. Inhibitors atvarying concentrations were pre-incubated with the reaction mixturecontaining SMPs for 4 min prior to initiation of the reaction. The IC₅₀value was determined as the concentration of the inhibitor required for50% inhibition of the NADH oxidation. The IC₅₀ value was calculatedusing GraphPad Prism Version 4 (GraphPad, San Diego, Calif.).

TABLE 1 MC1 inhibition data Example IC₅₀ (nM) flurpiridaz <100 1 >10003 >1000 4 >1000 5 >1000 6 >1000 7 <100 8 >1000 9 <100 12 ≤1000 16 ≤100017 ≤1000 18 ≤1000 19 ≤1000 20 <100 21 ≤1000 22 <100 23 ≤1000 25 <100 27<100 28 ≤1000 29 <100 31 >1000 32 <100 33 ≤1000 35 ≤1000 36 ≤1000 37<100 38 ≤1000 39 <100 40 <100 43 <100 45 <100 47 >1000 49 >1000 50 <10051 >1000 52 >1000 54 <100 55 <100 60 >4000 61 ≤1000 48B <100 48C ≤100053A >1000 53B >1000 56C <100 56D <100 57B <100 58A ≤1000 58B ≤100059D >4000 62A >1000 62B ≤1000 62C ≤1000 62D >1000

Example 65 Preparation of Imaging Agents Using a Custom Robotic DevicePart A—Preparation of [¹⁸F]Fluoride

[¹⁸F]Fluoride was produced by proton bombardment of [¹⁸O]H₂O in acyclotron; the nuclear chemical transformation is shown below and may besummarized as ¹⁸O(p,n)¹⁸F. For purposes of the bombardment, the chemicalform of the ₁₈O is H₂ ¹⁸O. The chemical form of the resulting ¹⁸F isfluoride ion.¹⁸O+proton→¹⁸F+neutron

According to established industry procedures, [¹⁸O]H₂O (2-3 mL) housedwithin a tantalum target body using Havar® foil, was bombarded with 11MeV protons (nominal energy); where the proton threshold energy for thereaction is 2.57 MeV and the energy of maximum cross section is 5 MeV.Target volume, bombardment time and proton energy each may be adjustedto manage the quantity of [¹⁸F]fluoride produced.

Part B—Preparation of Imaging Agents Using a Custom Robotic Device

[¹⁸F]Fluoride prepared according to Example 65A was applied to apreviously activated MP1 anion exchange resin (BioRad) contained withina small volume plastic housing. The loaded cartridge was then placedinto an elution loop located within a custom designed roboticradiosynthesis system and introduced when needed using one of thefollowing methods.

Method A: [¹⁸F]Fluoride (1 Ci) was transferred from the resin to a glassvessel using an aqueous solution of tetraethylammonium bicarbonate(1.1-1.3 molar equivalents). The resulting mixture was then concentratedto dryness at elevated temperature (120° C.) and reduced pressure.Anhydrous acetonitrile was then added to the concentrated solution andall volatiles removed once again using elevated temperature (70° C.) andreduced pressure.Method B: [¹⁸F]Fluoride (1 Ci) was transferred from the resin to a glassvessel using an aqueous solution of potassium bicarbonate (3 molarequivalents). The resulting mixture was then concentrated to dryness atelevated temperature (120° C.) and reduced pressure. A solution ofKryptofix™ (4 molar equivalents) in anhydrous acetonitrile was thenadded to the concentrated solution and all volatiles removed once againusing elevated temperature (70° C.) and reduced pressure.

A solution of the desired precursor (5-10 μmol) in anhydrousacetonitrile was then added to the glass reaction vessel in order tosolvate both [¹⁸F]fluoride and the remaining reaction components. Theresulting solution was then transferred to a new glass vessel, heated to90° C. and maintained 10 min. After cooling to ambient temperature, thesolution was diluted with water and directly purified by HPLC using aWaters Xterra C18 column (250×10 mm; 10μ) in combination with variousmixtures of water/acetonitrile for proper purification; both uv (220 nm)and radiation (NaI) detectors were utilized to determine the optimalpeak collection window. The purified product thus obtained wasconcentrated in vacuo then formulated in saline containing ≤10% ethanol.During routine preparation, ˜50 mCi of the fluorinated product wasprepared within 75 min.

TABLE 2 Synthetic parameters using a custom robotic device PrecursorExample Base K₂₂₂ RCY RCP 36 65A Et₄NHCO₃ No  5% 99% 36 65A KHCO₃ Yes 6% 99% 11 65B Et₄NHCO₃ No  1% Low 26 65C KHCO₃ Yes  7% 99% 14 65D KHCO₃Yes 13% Low

Example 66 Part A—Preparation of Imaging Agents Using the Explora RNChemistry Module

[¹⁸F]fluoride (1 Ci) produced according to Example 65A was transferredfrom cyclotron to the synthesis module then filtered through an anionexchange column (QMA, Waters, Inc.) to remove unreacted [¹⁸O]H₂O;[¹⁸F]fluoride was retained within the cationic resin matrix. The columnwas then washed with aqueous tetraethylammonium bicarbonate (1 molarequivalent) with transfer to the reaction vessel. The resulting solutionwas diluted with acetonitrile then concentrated to dryness; 150 mm Hg at115° C. for 4 min. The mixture of anhydrous [¹⁸F]tetraethylammoniumfluoride and tetraethylammonium bicarbonate thus obtained was treatedwith an acetonitrile solution of the required precursor (1 molarequivalent) then warmed to 90° C. and maintained 20 min.

Alternatively, [¹⁸F]fluoride (1 Ci) produced according to Example 65Awas transferred from cyclotron to the synthesis module then filteredthrough an anion exchange column (QMA, Waters, Inc.) to remove unreacted[¹⁸O]H₂O; [¹⁸F]fluoride was retained within the cationic resin matrix.The column was then washed with aqueous potassium carbonate (1 molarequivalent) with transfer to the reaction vessel. The resulting solutionwas treated with an acetonitrile solution of Kryptofix™ (2 molarequivalents) then concentrated to dryness; 150 mm Hg at 115° C. for 4min. The mixture of anhydrous [¹⁸F]potassium fluoride, potassiumcarbonate and Kryptofix™ thus obtained was treated with the requiredprecursor (1 molar equivalent; 10-50% dimethyl sulfoxide inacetonitrile) then warmed to 90-125° C. and maintained 10 min.

Alternatively, [¹⁸F]fluoride (1 Ci) produced according to Example 65Awas transferred from cyclotron to the synthesis module then filteredthrough a previously activated MP1 anion exchange resin (BioRad) toremove unreacted [¹⁸O]H₂O; [¹⁸F]fluoride was retained within thecationic resin matrix. The loaded cartridge was then placed into anelution loop located within a custom designed robotic radiosynthesissystem then washed with aqueous tetraethylammonium bicarbonate (1 molarequivalent) with transfer to the reaction vessel. The solution wasconcentrated to dryness at 280 mbar, 95-115° C., 4 min then treated withan acetonitrile solution of the required precursor (1 molar equivalent),warmed to 90° C. and maintained 10 min.

After cooling the crude reaction mixtures to 35° C., the resultingsolution was diluted with water then directly purified by HPLC on aWaters Xterra MS C18 column (10μ; 10×250 mm) using a water/acetonitrileeluent. The main product peak was collected, diluted with ascorbic acidthen formulated in 5% ethanol in ascorbic acid. During routinepreparation, ˜250 mCi of the fluorinated product was prepared.

TABLE 3 Synthetic parameters using the Explora RN chemistry modulePrecursor Example RCY RCP 10 66A 15% 99% 36 66B  4%^(a) 99% 34 66C 13%99% 15 66D 29% 99% 2 66E 33% 99% 41 66F 35% 99% 46 66G  6% 99% 57A 66H19% 99% 44 66I  5% 99% 48B 66J  9% 99% 61F 66K 20% 99% 62A 66L 14%^(a)99% 56C 66M 39% 99% ^(a)Combination of Kryptofix ™ and potassiumcarbonate was utilized.

Part B—Preparation of Imaging Agents Using the GE TracerLab MX ChemistryModule

FIG. 17 depicts a schematic representation of the preferred cassetteconfiguration used during the preparation of imaging agents on the GETracerLab MX chemistry module.

The product of Example 65A was transferred from cyclotron to thesynthesis module then filtered through an anion exchange column toremove unreacted [¹⁸O]H₂O; [¹⁸F]fluoride was retained within thecationic resin matrix. The column was then washed withtetraethylammonium bicarbonate (28.8 pmol; 0.500 mL of a 57.5 mMsolution in water) with transfer to the reaction vessel. The resultingsolution was diluted with acetonitrile then concentrated to dryness.Additional acetonitrile was then added and the drying process repeatedseveral times. The mixture of anhydrous tetraethylammonium fluoride andtetraethylammonium bicarbonate thus obtained was treated with theprecursor compound (23.0 μmol; 2.00 mL of a 11.5 mM solution inacetonitrile) then warmed to 90° C. and maintained 10 min. The resultingsolution was then diluted with water and directly purified by HPLC on aWaters Xterra MS C18 column using a water/acetonitrile eluent. The mainproduct peak was collected, diluted with ascorbic acid then filteredthrough a C18 Sep-Pak® cartridge to remove acetonitrile; the fluorinatedcompound was retained within the C18 resin matrix and the filtratediscarded. The loaded cartridge was successively washed with ascorbicacid, the filtrate discarded, then absolute ethanol, and the filtratecollected. The ethanol concentrate of the imaging agent thus obtainedwas further diluted with ascorbic acid then automatically delivered tothe final product vial through a 0.22 μm sterilizing filter.

2-(tert-Butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-onemay be prepared from2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl4-methylbenzenesulfonate in 52% radiochemical yield using the methoddescribed herein. An average decrease in drug product retention of 1.5%was observed using the revised cassette configuration described herein.

Part C—Preparation of imaging agents using the ORA NEPTIS ChemistryModule

FIG. 17 depicts a schematic representation of the preferred cassetteconfiguration used during the preparation of imaging agents on the ORANEPTIS chemistry module.

The product of Example 65A was transferred from cyclotron to thesynthesis module then filtered through an anion exchange column toremove unreacted [¹⁸O]H₂O; [¹⁸F]fluoride was retained within thecationic resin matrix. The column was then washed withtetraethylammonium bicarbonate (28.8 μmol; 0.500 mL of a 57.5 mMsolution in water) with transfer to the reaction vessel. The resultingsolution was diluted with acetonitrile then concentrated to dryness.Additional acetonitrile was then added and the drying process repeatedseveral times. The mixture of anhydrous tetraethylammonium fluoride andtetraethylammonium bicarbonate thus obtained was treated with theprecursor compound (23.0 μmol; 2.00 mL of a 11.5 mM solution inacetonitrile) then warmed to 90° C. and maintained 10 min. The resultingsolution was then diluted with water and directly purified by HPLC on aWaters Xterra MS C18 column using a water/acetonitrile eluent. The mainproduct peak was collected, diluted with ascorbic acid then filteredthrough a C18 Sep-Pak® cartridge to remove acetonitrile; the fluorinatedcompound was retained within the C18 resin matrix and the filtratediscarded. The loaded cartridge was successively washed with ascorbicacid, the filtrate discarded, then absolute ethanol, and the filtratecollected. The ethanol concentrate of the imaging agent thus obtainedwas further diluted with ascorbic acid then automatically delivered tothe final product vial through a 0.22 μm sterilizing filter.

2-(tert-Butyl)-4-chloro-5-((4-((2-fluoroethoxy)methyl)benzyl)oxy)pyridazin-3(2H)-onemay be prepared from2-((4-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)oxy)ethyl4-methylbenzenesulfonate in 48% radiochemical yield using the methoddescribed herein.

Example 67 Tissue Distribution and Imaging in Rats Part A—TissueDistribution

Anesthetized (sodium pentobarbital at 50 mg/kg, ip or isoflurane gasinhalation) Male Sprague Dawley rats (250-350 g) received an ivinjection of the imaging agent (˜15 μCi) via the tail vein. At 15 or 60min post injection, the animals were euthanized and the required tissuesamples harvested. All samples were then weighed and counted forradioactivity (Wallac Wizard 1480 or Packard Cobra II Autogamma);regional tissue uptake of the imaging agent was thus expressed as apercentage of the total injected dose per gram of tissue (% ID/g).

The generic structure depicted below highlights specific structuralfeatures evaluated during distribution experiments. Tables 4-6 summarizeresults from select studies.

TABLE 4 Structure correlation table Example R¹ R² R³ R⁴ R⁵ R⁶ J K M Y67A t-Bu Cl H CH₂O(CH₂)₂F H H O N/A N/A H 67B t-Bu Cl H H H H O N/A(CH₂)₂O(CH₂)₂F O 67C t-Bu Cl H Cl H H O N/A (CH₂)₃F O 67D t-Bu Cl H H HH O N/A (CH₂)₂F O 67E t-Bu Cl H H H H O D, D O(CH₂)₂F C 67F t-Bu Cl HO(CH₂)₂F H H O N/A N/A H 67G t-Bu Cl H H H H O CH₃, H O(CH₂)₂F C 67Hi-Pr Cl H H H H O H, H O(CH₂)₂F C 67I t-Bu CH₃ H H H H O H, H O(CH₂)₂F C67J t-Bu Cl H H H H O O O(CH₂)₂F C 67K t-Bu Cl H H H H O N/A C≡C(CH₂)₂Fbond 67L t-Bu Cl H H H H O N/A 2-fluoropyrimidin-5-yl bond 67M t-Bu Cl HH H H CH₂ H, H O(CH₂)₂F C 67N t-Bu Cl H H H H O t-Bu, t-Bu F Si 67O t-BuCl H H H H O N/A 2-fluoropyridin-3-yl O

TABLE 5 Summary of imaging agent distribution at 15 min (% ID/g ± SEM)Example Blood Liver Heart Lung Spleen 67A 0.03 ± 0.01 0.08 ± 0.03 0.65 ±0.36 0.07 ± 0.01 0.05 ± 0.01 67B 0.49 ± 0.02 2.33 ± 0.09 1.66 ± 0.060.49 ± 0.04 0.41 ± 0.01 67C 0.26 ± 0.05 2.67 ± 0.17 4.21 ± 0.29 0.50 ±0.08 0.37 ± 0.05 67D 1.11 3.61 3.63 1.00 0.37 67E 0.17 ± 0.02 0.66 ±0.09 4.80 ± 0.27 0.39 ± 0.05 0.36 ± 0.08 67F 0.32 ± 0.05 0.40 ± 0.041.92 ± 0.15 0.41 ± 0.03 0.28 ± 0.01 67G 0.50 ± 0.18 0.33 ± 0.10 2.19 ±0.36 0.46 ± 0.12 0.32 ± 0.11 67H 0.45 ± 0.02 0.46 ± 0.01 1.14 ± 0.090.41 ± 0.01 0.34 ± 0.03 67I 0.11 ± 0.02 0.33 ± 0.02 2.34 ± 0.57 0.19 ±0.03 0.18 ± 0.01 67J 0.50 ± 0.02 0.32 ± 0.01 1.19 ± 0.25 0.39 ± 0.020.34 ± 0.01 67K 0.07 ± 0.03 0.99 ± 0.06 2.68 ± 0.35 0.37 ± 0.15 0.31 ±0.09 67L 0.14 ± 0.01 1.71 ± 0.36 1.19 ± 0.18 0.29 ± 0.03 0.18 ± 0.01 67M0.53 ± 0.13 0.96 ± 0.10 2.54 ± 0.20 0.97 ± 0.13 0.35 ± 0.05 67N 0.22 ±0.04 4.91 ± 0.49 0.65 ± 0.09 1.31 ± 0.24 3.47 ± 0.80 67O 0.07 ± 0.030.99 ± 0.06 2.68 ± 0.35 0.37 ± 0.15 0.31 ± 0.09 Example Pancreas KidneyBrain Femur Muscle 67A 0.15 ± 0.05 0.38 ± 0.08 0.14 ± 0.05 0.06 ± 0.020.09 ± 0.04 67B N/A 2.25 ± 0.05 0.37 ± 0.02 0.80 ± 0.12 0.19 ± 0.00 67CN/A 3.04 ± 0.21 0.42 ± 0.01 0.33 ± 0.01 0.24 ± 0.04 67D N/A 3.81 0.740.21 0.14 67E 0.82 ± 0.07 2.61 ± 0.18 0.97 ± 0.11 0.50 ± 0.04 0.77 ±0.09 67F 0.52 ± 0.04 1.04 ± 0.10 0.50 ± 0.04 0.44 ± 0.04 0.60 ± 0.06 67G0.41 ± 0.03 0.88 ± 0.05 0.59 ± 0.03 0.40 ± 0.05 0.35 ± 0.04 67H 0.44 ±0.03 0.78 ± 0.01 0.43 ± 0.05 0.36 ± 0.04 0.38 ± 0.02 67I 0.43 ± 0.101.13 ± 0.11 0.49 ± 0.10 0.28 ± 0.04 0.28 ± 0.13 67J 0.23 ± 0.02 0.39 ±0.01 0.36 ± 0.01 0.28 ± 0.02 0.38 ± 0.04 67K 0.55 ± 0.10 1.35 ± 0.140.36 ± 0.04 0.27 ± 0.02 0.28 ± 0.02 67L 0.36 ± 0.06 0.65 ± 0.07 0.30 ±0.05 0.31 ± 0.01 0.27 ± 0.02 67M N/A 0.79 ± 0.07 0.55 ± 0.31 0.52 ± 0.190.24 ± 0.04 67N N/A 0.51 ± 0.09 0.03 ± 0.00 0.14 ± 0.02 0.06 ± 0.00 67O0.55 ± 0.10 1.35 ± 0.14 0.36 ± 0.04 0.27 ± 0.02 0.28 ± 0.02

TABLE 6 Summary of imaging agent distribution at 60 min (% ID/g ± SEM)Example Blood Liver Heart Lung Spleen 67A 0.11 ± 0.02 0.11 ± 0.02 0.84 ±0.22 0.11 ± 0.02 0.09 ± 0.02 67B 0.26 ± 0.04 1.34 ± 0.22 1.58 ± 0.130.27 ± 0.03 0.20 ± 0.04 67C 0.20 ± 0.07 0.65 ± 0.12 4.54 ± 0.29 0.61 ±0.32 0.18 ± 0.02 67D 1.00 1.49 4.66 0.96 0.23 67E 0.26 ± 0.03 0.53 ±0.06 3.61 ± 0.45 0.34 ± 0.03 0.25 ± 0.01 67F 0.48 ± 0.01 0.39 ± 0.040.87 ± 0.02 0.44 ± 0.03 0.31 ± 0.01 67G 0.47 ± 0.04 0.32 ± 0.03 0.98 ±0.16 0.38 ± 0.03 0.28 ± 0.03 67H 0.55 ± 0.02 0.40 ± 0.02 0.55 ± 0.030.42 ± 0.01 0.35 ± 0.02 67I 0.16 ± 0.01 0.30 ± 0.01 1.78 ± 0.15 0.19 ±0.01 0.13 ± 0.00 67J 0.58 ± 0.04 0.35 ± 0.02 0.50 ± 0.03 0.42 ± 0.020.37 ± 0.02 67K 0.03 ± 0.00 0.83 ± 0.17 2.46 ± 0.27 0.15 ± 0.03 0.11 ±0.02 67L 0.10 ± 0.02 2.06 ± 0.27 0.62 ± 0.12 0.21 ± 0.02 0.11 ± 0.02 67M0.73 ± 0.16 0.43 ± 0.04 0.55 ± 0.06 1.03 ± 0.22 0.26 ± 0.03 67O 0.03 ±0.00 0.83 ± 0.17 2.46 ± 0.27 0.15 ± 0.03 0.11 ± 0.02 Example PancreasKidney Brain Femur Muscle 67A 0.13 ± 0.03 0.23 ± 0.03 0.14 ± 0.03 0.17 ±0.04 0.18 ± 0.04 67B N/A 1.17 ± 0.20 0.30 ± 0.02 0.78 ± 0.22 0.15 ± 0.0467C N/A 1.77 ± 0.25 0.44 ± 0.03 0.84 ± 0.07 0.26 ± 0.02 67D N/A 1.710.69 0.26 0.18 67E 0.43 ± 0.05 0.98 ± 0.04 0.62 ± 0.04 0.69 ± 0.05 0.69± 0.17 67F 0.48 ± 0.01 0.60 ± 0.03 0.38 ± 0.01 0.57 ± 0.04 0.43 ± 0.0767G 0.26 ± 0.01 0.44 ± 0.02 0.39 ± 0.05 0.58 ± 0.06 0.33 ± 0.01 67H 0.32± 0.02 0.49 ± 0.03 0.43 ± 0.02 0.71 ± 0.06 0.31 ± 0.02 67I 0.23 ± 0.020.48 ± 0.04 0.36 ± 0.01 0.31 ± 0.02 0.35 ± 0.09 67J 0.23 ± 0.03 0.42 ±0.02 0.43 ± 0.02 0.40 ± 0.03 0.31 ± 0.02 67K 0.38 ± 0.02 0.83 ± 0.080.36 ± 0.03 0.37 ± 0.05 0.39 ± 0.04 67L 0.33 ± 0.08 0.40 ± 0.08 0.22 ±0.03 0.78 ± 0.15 0.20 ± 0.06 67M N/A 0.43 ± 0.04 2.33 ± 0.12 0.43 ± 0.030.31 ± 0.04 67O 0.38 ± 0.02 0.83 ± 0.08 0.36 ± 0.03 0.37 ± 0.05 0.39 ±0.04

Part B—PET Imaging and Data Reconstruction

PET imaging was performed in Male Sprague Dawley rats anesthetized asoutlined above. The animal was then positioned in a microPET camera(Focus220, CTI Molecular Imaging or Philips MOSAIC HP) and injected withthe imaging agent (˜1 mCi) via a tail vein catheter. Image acquisitionwas initiated immediately following injection and was terminated at 60min. Following acquisition, the images were reconstructed in a matrix of256×256 or 128×128 pixels (microPET Manager and ASIPro or PETview,respectively) and decay corrected. Serial tomographic images were thusgenerated using 5 or 10 min intervals.

FIG. 1 shows representative images of [¹⁸F]67A in rat.

FIG. 2 shows representative images of [¹⁸F]67B in rat.

FIG. 3 shows representative images of [¹⁸F]67C in rat.

FIG. 4 shows representative images of [¹⁸F]67D in rat.

FIG. 5 shows representative images of [¹⁸F]67E in rat.

FIG. 6 shows representative images of [¹⁸F]67F in rat.

FIG. 7 shows representative images of [¹⁸F]67G in rat.

FIG. 8 shows representative images of [¹⁸F]67H in rat.

FIG. 9 shows representative images of [¹⁸F]67I in rat.

FIG. 10 shows representative images of [¹⁸F]67J in rat.

FIG. 11 shows representative images of [¹⁸F]67K in rat.

FIG. 12 shows representative images of [¹⁸F]67L in rat.

FIG. 13 shows representative images of [¹⁸F]67M in rat.

FIG. 14 shows representative images of [¹⁸F]67N in rat.

FIG. 15 shows representative images of [¹⁸F]670 in rat.

Example 68 Metabolic Profiling of Imaging Agents Part A—HepatocytePreparation

Cryopreserved hepatocytes were purchased from Celsis/In VitroTechnologies, Inc. (Baltimore, Md.) and stored at −150° C. prior to use.Multiple lots of hepatocytes for human (mixed sexes 5-donor pool),primate (male, rhesus monkey), dog (male, beagle), rabbit (male, NewZealand white) and rat (male, Sprague-Dawley) were used. On the day ofthe study, hepatocytes in cryopreserved vials were vented to release anyliquid N2 then placed into a 37° C. water bath for 75-90 seconds tothaw. The hepatocytes were transferred into pre-warmed KHB andcentrifuged for 5 min at 50×g. The supernatant was discarded and thehepatocytes re-suspended in KHB at a concentration of 1×10⁶ cells/mL.Cell viability was confirmed by Trypan blue exclusion.

Part B—Hepatocyte Incubation

Test compounds were incubated in hepatocytes (1×10⁶ cells/mL; 0.5 mL)were incubated for 0, 15, 30, 60 or 180 min at 37° C./5% CO₂ thentransferred directly into acetonitrile (1.0 mL), vortexed for 30 s andcentrifuged at 2500×g for 20 min. The supernatant was then transferredto a new centrifuge tube, acetonitrile evaporated under a stream ofnitrogen in a heating block at 37° C. and, following re-constitution inwater, assayed by HPLC with radiodetection.

Part C—HPLC Analysis

Extracted samples and standards were analyzed on an Agilent 1100 HPLC(Agilent Technologies, Burlington, Mass.) using a Phenomenex Luna C18column (5μ; 4.6×150 mm), maintained at ambient temperature (25° C.), anda flow rate of 1.0 mL/min. Mobile phase A contained 0.1% formic acid inwater, and mobile phase B contained 0.1% formic acid in acetonitrile. Alinear gradient from 5 to 90% B over 15 min was used for elution. A 5min post-time of 5% B was used to re-equilibrate the column. Radioactiveproducts were recorded using in-line 7- or f3-flow detectors (INUS,Tampa, Fla.).

Imaging % Parent Agent Remaining 35 30 25 71 9 73 16 20 1 20 45 19 40 3457B 31 43 63 48C 95 61G 6 62B 98

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element or a list of elements. In general, the term “or” as usedherein shall only be interpreted as indicating exclusive alternatives(i.e. “one or the other but not both”) when preceded by terms ofexclusivity, such as “either,” “one of,” “only one of,” or “exactly oneof.” “Consisting essentially of,” when used in the claims, shall haveits ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

What is claimed:
 1. A cassette for the preparation of an imaging agentcomprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order: 1) ethanol reservoir; 2) syringe with a solutionof ascorbic acid or salt thereof; 3) syringe with water; and 4) finalproduct vial; wherein the imaging agent is of the formula:


2. The cassette of claim 1, comprising a linear arrangement of aplurality of stopcock manifolds arranged in the order: 1) luerconnections (2) to gas inlet and [18O]H2O recovery; 2) anion exchangecartridge—column eluting solution; 3) spike connection for acetonitrile;4) empty syringe; 5) reservoir with a solution of imaging agentprecursor; 6) reaction vessel; 7) outlet to HPLC; 8) syringe withsolution of ascorbic acid or salt thereof; 9) inlet from HPLC; 10)ethanol reservoir; 11) syringe with a solution of ascorbic acid or saltthereof; 12) syringe with water; and 13) final product vial.
 3. Thecassette of claim 1, comprising a linear arrangement of a plurality ofstopcock manifolds arranged in the order: 1) ethanol reservoir; 2)syringe with a solution of ascorbic acid or salt thereof; 3) syringewith water; 4) final product vial; 5) empty syringe; and 6) reactionvessel and exhaust.
 4. The cassette of claim 1, comprising a lineararrangement of a plurality of stopcock manifolds arranged in theorder: 1) luer connections (2) to gas inlet and [18O]H2O recovery; 2)anion exchange cartridge—column eluting solution; 3) spike connectionfor acetonitrile; 4) empty syringe; 5) reservoir with a solution ofimaging agent precursor; 6) reaction vessel; 7) outlet to HPLC; 8)syringe with solution of ascorbic acid or salt thereof; 9) inlet fromHPLC; 10) ethanol reservoir; 11) syringe with a solution of ascorbicacid or salt thereof; 12) syringe with water; 13) final product vial;14) empty syringe; and 15) reaction vessel and exhaust.
 5. The cassetteof claim 1, wherein the solution of ascorbic acid or salt thereof is ata pH of about 2 or about 5.8.
 6. An apparatus for synthesizing animaging agent comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order: 1) ethanol reservoir; 2) syringe withsolution of ascorbic acid or salt thereof; 3) syringe with water; 4)final product vial.
 7. The apparatus of claim 6, comprising a lineararrangement of a plurality of stopcock manifolds arranged in theorder: 1) luer connections (2) to gas inlet and [18O]H2O recovery; 2)anion exchange cartridge—column eluting solution; 3) spike connectionfor acetonitrile; 4) empty syringe; 5) reservoir with solution ofimaging agent precursor; 6) reaction vessel; 7) outlet to HPLC; 8)syringe with solution of ascorbic acid or salt thereof; and 9) inletfrom HPLC.
 8. The apparatus of claim 6, comprising a linear arrangementof a plurality of stopcock manifolds arranged in the order: 1) luerconnections (2) to gas inlet and [18O]H2O recovery; 2) anion exchangecartridge—column eluting solution; 3) reservoir with solution of imagingagent precursor; 4) empty syringe; 5) spike connection for acetonitrile;6) reaction vessel; 7) outlet to HPLC; 8) syringe with solution ofascorbic acid or salt thereof; and 9) inlet from HPLC.
 9. The apparatusof claim 6, comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order: 1) ethanol reservoir; 2) syringe withsolution of ascorbic acid or salt thereof; 4) syringe with water; 5)final product vial; 6) empty syringe; and 7) reaction vessel andexhaust.
 10. The apparatus of claim 6, comprising a linear arrangementof a plurality of stopcock manifolds arranged in the order: 1) luerconnections (2) to gas inlet and [18O]H2O recovery; 2) anion exchangecartridge—column eluting solution; 3) spike connection for acetonitrile;4) empty syringe; 5) reservoir with solution of imaging agent precursor;6) reaction vessel; 7) outlet to HPLC; 8) syringe with solution ofascorbic acid or salt thereof; 9) inlet from HPLC; 10) ethanolreservoir; 11) syringe with solution of ascorbic acid or salt thereof;12) syringe with water; 13) final product vial; 14) empty syringe; and15) reaction vessel and exhaust.
 11. The apparatus of claim 6,comprising a linear arrangement of a plurality of stopcock manifoldsarranged in the order: 1) luer connections (2) to gas inlet and [18O]H2Orecovery; 2) anion exchange cartridge—column eluting solution; 3)reservoir with solution of imaging agent precursor; 4) empty syringe; 5)spike connection for acetonitrile; 6) reaction vessel; 7) outlet toHPLC; 8) syringe with solution of a stabilizing agent; 9) inlet fromHPLC; 10) ethanol reservoir; 11) syringe with solution of a stabilizingagent; 12) syringe with water; 13) final product vial; 14) emptysyringe; and 15) reaction vessel and exhaust.
 12. The apparatus of claim6, wherein the apparatus is capable of preparing an imaging agent of theformula:


13. An apparatus for synthesizing an imaging agent comprising a lineararrangement of a plurality of stopcock manifolds arranged in theorder: 1) ethanol reservoir; 2) final product vial; 3) syringe withwater; and 4) syringe with solution of ascorbic acid or salt thereof.14. The apparatus of claim 13, comprising a linear arrangement of aplurality of stopcock manifolds arranged in the order: 1) luerconnections (2) to gas inlet and [18O]H2O recovery; 2) anion exchangecartridge—column eluting solution; 3) reservoir with solution of imagingagent precursor; 4) empty syringe; 5) spike connection for acetonitrile;6) reaction vessel; 7) outlet to HPLC; 8) syringe with solution ofascorbic acid or salt thereof; and 9) inlet from HPLC.
 15. The apparatusof claim 13, comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order: 1) luer connections (2) to gas inletand [18O]H2O recovery; 2) anion exchange cartridge—column elutingsolution; 3) spike connection for acetonitrile; 4) empty syringe; 5)reservoir with solution of imaging agent precursor; 6) reaction vessel;7) outlet to HPLC; 8) syringe with solution of ascorbic acid or saltthereof; and) inlet from HPLC.
 16. The apparatus of claim 13, comprisinga linear arrangement of a plurality of stopcock manifolds arranged inthe order: 1) ethanol reservoir; 2) final product vial; 3) syringe withwater; 4) syringe with solution of ascorbic acid or salt thereof; 5)empty syringe; and 6) reaction vessel and exhaust.
 17. The apparatus ofclaim 13, comprising a linear arrangement of a plurality of stopcockmanifolds arranged in the order: 1) luer connections (2) to gas inletand [18O]H2O recovery; 2) anion exchange cartridge—column elutingsolution; 3) reservoir with solution of imaging agent precursor; 4)empty syringe; 5) spike connection for acetonitrile; 6) reaction vessel;7) outlet to HPLC; 8) syringe with solution of ascorbic acid or saltthereof; 9) inlet from HPLC; 10) ethanol reservoir; 11) final productvial; 12) syringe with water; 13) syringe with solution of ascorbic acidor salt thereof 14) empty syringe; and 15) reaction vessel and exhaust.18. The apparatus of claim 13, comprising a linear arrangement of aplurality of stopcock manifolds arranged in the order: 1) luerconnections (2) to gas inlet and [18O]H2O recovery; 2) anion exchangecartridge—column eluting solution; 3) spike connection for acetonitrile;4) empty syringe; 5) reservoir with solution of imaging agent precursor;6) reaction vessel; 7) outlet to HPLC; 8) syringe with solution ofascorbic acid or salt thereof; 9) inlet from HPLC; 10) ethanolreservoir; 11) final product vial; 12) syringe with water; 13) syringewith solution of ascorbic acid or salt thereof; 14) empty syringe; and15) reaction vessel and exhaust.
 19. The apparatus of claim 13, whereinthe apparatus is capable of preparing an imaging agent of the formula: